Quinoline derivatives and their use as aurora 2 kinase inhibitors

ABSTRACT

A compound of formula (I) 
                 
 
or a salt, ester, amide or prodrug thereof; R 5  is an optionally substituted 6-membered aromatic ring containing at least one nitrogen atom, and R 1 , R 2 , R 3 , R 4  are independently selected from halogeno, cyano, nitro, C 1-3 alkylsulphonyl, —N(OH)R 7 — (wherein R 7  is hydrogen, or C 1-3  alkyl), or R 9 X 1 — (wherein X 1  represents a direct bond, —O—, —CH 2 —, —OC(O)—, —C(O)—, —S—, —SO—, —SO 2 —, —NR 10 C(O)—, —C(O)NR 11 —, —SO 2 NR 12 —, —NR 13 SO 2 — or —NR 14 — (wherein R 10 , R 11 , R 12 , R 13  and R 14  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and R 9  is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy); provided that at least one of R 2  or R 3  is other than hydrogen. These compounds are inhibitors of aurora 2 kinase. Thus they, and pharmaceutical compositions containing them, are useful in methods of treatment of proliferative disease such as cancer and in particular cancers such as colorectal or breast cancer where aurora 2 is upregulated.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 of PCTapplication PCT/GB01/00245, filed Jan. 24, 2001, which claims priorityto European Application No. 00400228.3, filed Jan. 28, 2000, thespecifications of each of which are incorporated by reference herein.PCT Application PCT/GB01/00245 was published under PCT Article 21(2) inEnglish.

The present invention relates to novel quinoline derivatives useful inthe treatment of certain diseases in particular to proliferative diseasesuch as cancer, to process for their preparation, as well aspharmaceutical compositions containing them as active ingredient.

Cancer (and other hyperproliferative disease) is characterised byuncontrolled cellular proliferation. This loss of the normal regulationof cell proliferation often appears to occur as the result of geneticdamage to cellular pathways that control progress through the cellcycle.

In eukaryotes, the cell cycle is largely controlled by an orderedcascade of protein phosphorylation. Several families of protein kinasesthat play critical roles in this cascade have now been identified. Theactivity of many of these kinases is increased in human tumours whencompared to normal tissue. This can occur by either increased levels ofexpression of the protein (as a result of gene amplification forexample), or by changes in expression of co activators or inhibitoryproteins.

The first identified, and most widely studied of these cell cycleregulators have been the cyclin dependent kinases (or CDKs). Activity ofspecific CDKs at specific times is essential for both initiation andcoordinated progress through the cell cycle For example, the CDK4protein appears to control entry into the cell cycle (the G0-G1-Stransition) by phosphorylating the retinoblastoma gene product pRb. Thisstimulates the release of the transcription factor E2F from pRb, whichthen acts to increase the transcription of genes necessary for entryinto S phase. The catalytic activity of CDK4 is stimulated by binding toa partner protein, Cyclin D. One of the first demonstrations of a directlink between cancer and the cell cycle was made with the observationthat the Cyclin D1 gene was amplified and cyclin D protein levelsincreased (and hence the activity of CDK4 increased) in many humantumours (Reviewed in Sherr, 1996, Science 274: 1672-1677; Pines, 1995,Seminars in Cancer Biology 6: 63-72). Other studies (Loda et al., 1997,Nature Medicine 3(2): 231-234; Gemma et al., 1996, International Journalof Cancer 68(5): 605-11; Elledge et al. 1996, Trends in Cell Biology 6;388-392) have shown that negative regulators of CDK function arefrequently down regulated or deleted in human tumours again leading toinappropriate activation of these kinases.

More recently, protein kinases that are structurally distinct from theCDK family have been identified which play critical roles in regulatingthe cell cycle and which also appear to be important in oncogenesis.These include the newly identified human homologues of the Drosophilaaurora and S. cerevisiae Ipl1 proteins. Drosophila aurora and S.cerevisiae Ipl1, which are highly homologous at the amino acid sequencelevel, encode serine/threonine protein kinases. Both aurora and Ipl1 areknown to be involved in controlling the transition from the G2 phase ofthe cell cycle through mitosis, centrosome function, formation of amitotic spindle and proper chromosome separation/segregation intodaughter cells. The two human homologues of these genes, termed aurora1and aurora2, encode cell cycle regulated protein kinases. These show apeak of expression and kinase activity at the G2/M boundary (aurora2)and in mitosis itself (aurora1). Several observations implicate theinvolvement of human aurora proteins, and particularly aurora2 incancer. The aurora2 gene maps to chromosome 20q13, a region that isfrequently amplified in human tumours including both breast and colontumours. Aurora2 may be the major target gene of this amplicon, sinceaurora2 DNA is amplified and aurora2 mRNA overexpressed in greater than50% of primary human colorectal cancers. In these tumours aurora2protein levels appear greatly elevated compared to adjacent normaltissue. In addition, transfection of rodent fibroblasts with humanaurora2 leads to transformation, conferring the ability to grow in softagar and form tumours in nude mice (Bischoff et al., 1998, The EMBOJournal. 17(11): 3052-3065). Other work (Zhou et al., 1998, NatureGenetics. 20(2): 189-93) has shown that artificial overexpression ofaurora2 leads to an increase in centrosome number and an increase inaneuploidy.

Importantly, it has also been demonstrated that abrogation of aurora2expression and function by antisense oligonucleotide treatment of humantumour cell lines (WO 97/22702 and WO 99/37788) leads to cell cyclearrest in the G2/M phase of the cell cycle and exerts anantiproliferative effect in these tumour cell lines. There isconsiderable evidence that G2/M arrest, resulting (for example) fromdisruption of assembly of the mitotic spindle by microtubule bindingdrugs such as paclitaxel leads to the induction of apoptosis in tumourcells in a manner distinct from inhibition of e.g. the EGF receptor,(Kottke et al. 1999 Journal of Biological Chemistry 274 (22)15927-15936, reviewed in Blagosklonny et ql., 1999, InternationalJournal of Cancer 83: 151-156). This indicates that inhibition of thefunction of aurora2 will have an antiproliferative effect, and may havean apoptosisinducing effect, that may be useful in the treatment ofhuman tumours and other hyperproliferative diseases

Certain heterocyclic derivatives have been proposed hitherto for use inthe inhibition of protein tyrosine kinase in WO 99/35132.

The applicants have found a series of compounds which inhibit the effectof the aurora2 kinase and which are thus of use in the treatment ofproliferative disease such as cancer, in particular in such diseasessuch as colorectal or breast cancer where aurora 2 kinase is known to beactive.

The present invention provides a compound of formula (I)

or a salt, ester, amide or prodrug thereof;

-   where R⁵ is an optionally substituted 6-membered aromatic ring    containing at least one nitrogen atom, and-   R¹, R², R³, R⁴ are independently selected from halogeno, cyano,    nitro, C₁₋₃alkylsulphanyl, —N(OH)R⁷— (wherein R⁷ is hydrogen, or    C₁₋₃alkyl), or R⁹X¹— (wherein X¹ represents a direct bond, —O—,    —CH₂—, —OC(O)—, —C(O)—, —S—, —SO—, —SO₂—, —NR¹⁰C(O)—, —C(O)NR¹¹—,    —SO₂NR¹²—, —NR¹³SO₂— or —NR¹⁴— (wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴    each independently represents hydrogen, C₁₋₃alkyl, hydroxyC₁₋₄alkyl    or C₁₋₃alkoxyC₂₋₃alkyl), and R⁹ is hydrogen, optionally substituted    hydrocarbyl, optionally substituted heterocyclyl or optionally    substituted alkoxy; provided that at least one of R² or R³ is other    than hydrogen.

In this specification the term ‘alkyl’ when used either alone or as asuffix includes straight chained, branched structures. Unless otherwisestated, these groups may contain up to 10, preferably up to 6 and morepreferably up to 4 carbon atoms. Similarly the terms “alkenyl” and“alkynyl” refer to unsaturated straight or branched structurescontaining for example from 2 to 10, preferably from 2 to 6 carbonatoms. Cyclic moieties such as cycloalkyl, cycloalkenyl and cycloalkynylare similar in nature but have at least 3 carbon atoms. Terms such as“alkoxy” comprise alkyl groups as is understood in the art.

The term “halo” includes fluoro, chloro, bromo and iodo. References toaryl groups include aromatic carbocylic groups such as phenyl andnaphthyl. The term “heterocyclyl” includes aromatic or non-aromaticrings, for example containing from 4 to 20, suitably from 5 to 8 ringatoms, at least one of which is a heteroatom such as oxygen, sulphur ornitrogen. Examples of such groups include furyl, thienyl, pyrrolyl,pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl,isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl,benzoxazolyl, benzothienyl or benzofuryl. Examples of non-aromaticheterocyclyl groups include morpholino, piperidino, azetidine,tetrahydrofuryl, tetrahydropyridyl. In the case of bicyclic rings, thesemay comprise an aromatic and non-aromatic portion.

“Heteroaryl” refers to those groups described above which have anaromatic character. The term “aralkyl” refers to aryl substituted alkylgroups such as benzyl.

Other expressions used in the specification include “hydrocarbyl” whichrefers to any structure comprising carbon and hydrogen atoms. The moietymay be saturated or unsaturated. For example, these may be alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl orcycloalkynyl, or combinations thereof.

Examples of such combinations are alkyl, alkenyl or alkynyl substitutedwith aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, or anaryl, heterocyclyl, alkoxy, aralkyl, cycloalkyl, cycloalkenyl orcycloalkynyl substituted with alkyl, alkenyl, alkynyl or alkoxy, butothers may be envisaged.

In particular hydrocarbyl groups include alkyl, alkenyl, alkynyl, aryl,aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.

The term “functional group” refers to reactive substituents such asnitro, cyano, halo, oxo, ═CR⁷⁸R⁷⁹, C(O)_(x)R⁷⁷, OR⁷⁷, S(O)_(y)R⁷⁷,NR⁷⁸R⁷⁹, C(O)NR⁷⁸R⁷⁹, OC(O)NR⁷⁸R⁷⁹, ═NOR⁷⁷, —NR⁷⁷C(O)_(x)R⁷⁸,—NR⁷⁷CONR⁷⁸R⁷⁹, —N═CR⁷⁸R⁷⁹, S(O)_(y)NR⁷⁸R⁷⁹ or —NR⁷⁷S(O)_(y)R⁷⁸ whereR⁷⁷, R⁷⁸ and R⁷⁹ are independently selected from hydrogen, optionallysubstituted hydrocarbyl, optionally substituted hetercyclyl oroptionally substituted alkoxy, or R⁷⁸ and R⁷⁹ together form anoptionally substituted ring which optionally contains furtherheteroatoms such as oxygen, nitrogen, S, S(O) or S(O)₂, where x is aninteger of 1 or 2, y is 0 or an integer of 1-3.

Suitable optional substituents for hydrocarbyl, heterocyclyl or alkoxygroups R⁷⁷, R⁷⁸ and R⁷⁹ as well as rings formed by R⁷⁸ and R⁷⁹ includehalo, perhaloalkyl such as trifluoromethyl, mercapto, thioalkyl,hydroxy, carboxy, alkoxy, heteroaryl, heteroaryloxy, cycloalkyl,cycloalkenyl, cycloalkynyl, alkenyloxy, alkynyloxy, alkoxyalkoxy,aryloxy (where the aryl group may be substituted by halo, nitro, orhydroxy), cyano, nitro, amino, mono- or di-alkyl amino, oximino orS(O)_(y)R⁹⁰ where y is as defined above and R⁹⁰ is a hydrocarbyl groupsuch as alkyl.

In particular, optional substituents for hydrocarbyl, hetercyclyl oralkoxy groups R⁷⁷, R⁷⁸ and R⁷⁹ include halo, perhaloalkyl such astrifluoromethyl, mercapto, hydroxy, carboxy, alkoxy, heteroaryl,heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, aryloxy (where thearyl group may be substituted by halo, nitro, or hydroxy), cyano, nitro,amino, mono- or di-alkyl amino, oximino or S(O)_(y)R⁹⁰ where y is asdefined above and R⁹⁰ is a hydrocarbyl group such as alkyl.

Certain compounds of formula (I) may include a chiral centre and theinvention includes all enantiomeric forms thereof, as well as mixturesthereof including racemic mixtures.

In particular, R⁹ is hydrogen or an alkyl group, optionally substitutedwith one or more groups selected from functional groups as definedabove, or alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, cycloalkenylor cycloalkynyl, any of which may be substituted with a functional groupas defined above, and where any aryl, heterocyclyl, cycloalkyl,cycloalkenyl, cycloalkynyl groups may also be optionally substitutedwith hydrocarbyl such as alkyl, alkenyl or alkynyl.

For example, R⁹ is selected from one of the following twenty-two groups:

-   1) hydrogen or C₁₋₅alkyl which may be unsubstituted or which may be    substituted with one or more functional groups;-   2) —R^(a)X²C(O)R¹⁵ (wherein X² represents —O— or —NR¹⁶— (in which    R¹⁶ represents hydrogen, or alkyl optionally substituted with a    functional group) and R¹⁵ represents C₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹    (wherein R¹⁷, R¹⁸ and R¹⁹ which may be the same or different each    represents hydrogen, or alkyl optionally substituted with a    functional group);-   3) —R^(b)X³R²⁰ (wherein X³ represents —O—, —C(O)—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR²¹C(O)_(s)—, —C(O)NR²²—, —SO₂NR²³—, —NR²⁴SO₂— or —NR²⁵—    (wherein R²¹, R²², R²³, R²⁴ and R²⁵ each independently represents    hydrogen, or alkyl optionally substituted with a functional group    and s is 1 or 2) and R²⁰ represents hydrogen, hydrocarbyl (as    defined herein) or a saturated heterocyclic group, wherein the    hydrocarbyl or heterocyclic groups may be optionally substituted by    one or more functional groups and the heterocyclic groups may    additionally be substituted by a hydrocarbyl group;-   4) —R^(c)X⁴R^(c′)X⁵R²⁶ (wherein X⁴ and X⁵ which may be the same or    different are each —O—, —C(O)—, —S—, —SO—, —SO₂—, —OC(O)—,    —NR²⁷C(O)_(s)—, —C(O)_(x)NR²⁸—, —SO₂NR²⁹—, —NR³⁰SO₂— or —NR³¹—    (wherein R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ each independently represents    hydrogen or alkyl optionally substituted by a functional group and s    is 1 or 2) and R²⁶ represents hydrogen, or alkyl optionally    substituted by a functional group;-   5) R³² wherein R³² is a C₃₋₆ cycloalkyl or saturated heterocyclic    ring (linked via carbon or nitrogen), which cycloalkyl or    heterocyclic group may be substituted by one or more functional    groups or by a hydrocarbyl or heterocyclyl group which hydrocarbyl    or heterocyclyl group may be optionally substituted by one or more    functional groups;-   6) —R^(d)R³² (wherein R³² is as defined hereinbefore);-   7) —R^(e)R³² (wherein R³² is as defined hereinbefore);-   8) —R^(f)R³² (wherein R³² is as defined hereinbefore);-   9) R³³ (wherein R³³ represents a pyridone group, an aryl group or an    aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3    heteroatoms selected from O, N and S, which pyridone, aryl or    aromatic heterocyclic group may be substituted by one or more    functional groups or by a hydrocarbyl group optionally substituted    by one or more functional groups or heterocyclyl groups, or by a    heterocyclyl group optionally susbsituted by one or more functional    groups or hydrocarbyl groups;-   10) —R^(g)R³³ (wherein R³³ is as defined hereinbefore);-   11) —R^(h)R³³ (wherein R³³ is as defined hereinbefore);-   12) —R^(i)R³³ (wherein R³³ is as defined hereinbefore);-   13) —R^(j)X⁶R³³ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,    —OC(O)—, —NR³⁸C(O)—, —C(O)NR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²—    (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² each independently represents    hydrogen, or alkyl optionally substituted with a functional group)    and R³⁷ is as defined hereinbefore);-   14) —R^(k)X⁷R³³ (wherein X⁷ represents —O—, —C(O)—, —S—, —SO—,    —SO₂—, —OC(O)—, —NR⁴³C(O)—, —C(O)NR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or    —NR⁴⁷— (wherein R⁴³, R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ each independently    represents hydrogen, or alkyl optionally substituted with a    functional group) and R³³ is as defined hereinbefore);-   15) —R^(m)X⁸R³³ (wherein X⁸ represents —O—, —C(O)—, —S—, —SO—,    —SO₂—, —OC(O)—, —NR⁴⁸C(O)—, —C(O)NR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or    —NR⁵²— (wherein R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹ and R⁵² each independently    represents hydrogen, hydrogen, or alkyl optionally substituted with    a functional group) and R³³ is as defined hereinbefore);-   16) —R^(n)X⁹R^(n′)R³³ (wherein X⁹ represents —O—, —C(O)—, —S—, —SO—,    —SO₂—, —OC(O)—, —NR⁵³C(O)—, —C(O)NR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or    —NR⁵⁷— (wherein R⁵³, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ each independently    represents hydrogen, hydrogen, or alkyl optionally substituted with    a functional group) and R³³ is as defined hereinbefore);-   17) —R^(p)X⁹—R^(p′)R³² (wherein X⁹ and R³² are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more functional groups;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more functional groups;-   20) —R^(t)X⁹R^(t′)R³² (wherein X⁹ and R³² are as defined    hereinbefore);-   21) —R^(u)X⁹R^(u′)R³² (wherein X⁹ and R³² are as defined    hereinbefore); and-   22) —R^(v)R⁵⁸(R^(v′))_(q)(X⁹)_(r)R⁵⁹ (wherein X⁹ is as defined    hereinbefore, q is 0 or 1, r is 0 or 1, and R⁵⁸ is a C₁₋₃alkylene    group or a cyclic group selected from divalent cycloalkyl or    heterocyclic group, which C₁₋₃alkylene group may be substituted by    one or more functional groups and which cyclic group may be    substituted by one or more functional groups or by a hydrocarbyl    group optionally substituted by one or more functional groups or    heterocyclyl groups, or by a heterocyclyl group optionally    substituted by one or more functional groups or hydrocarbyl groups;    and R⁵⁹ is hydrogen, C₁₋₃alkyl, or a cyclic group selected from    cycloalkyl or heterocyclic group, which C₁₋₃alkylene group may be    substituted by one or more functional groups and which cyclic group    may be substituted by one or more may be substituted by one or more    functional groups or by a hydrocarbyl group optionally substituted    by one or more functional groups or heterocyclyl groups, or by a    heterocyclyl group optionally substituted by one or more functional    groups or hydrocarbyl groups;-   and wherein R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), Rg, R^(j),    R^(n), R^(n′), R^(p), R^(p′), R^(t′), R^(u′), R^(v) and R^(v′) are    independently selected from C₁₋₈alkylene groups optionally    substituted by one or more substituents functional groups,-   R^(e)R^(h), R^(k) and R^(t) are independently selected from    C₂₋₈alkenylene groups optionally substituted by one or more    functional groups, and-   R^(f), R^(i), R^(m) and R^(u) are independently selected from by    C₂₋₈alkynylene groups optionally substituted by one or more    functional groups.

For example, R⁹ is selected from one of the following twenty-two groups:

-   1) hydrogen or C₁₋₅alkyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, oxiranyl,    fluoro, chloro, bromo and amino (including C₁₋₃alkyl and    trifluoromethyl);-   2) —R^(a)X²C(O)R¹⁵ (wherein X² represents —O— or —NR¹⁶— (in which    R¹⁶ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁵    represents C₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹ (wherein R¹⁷, R¹⁸ and R¹⁹    which may be the same or different each represents hydrogen,    C₁₋₅alkyl. hydroxyC₁₋₅alkylor C₁₋₃alkoxyC₂₋₃alkyl));-   3) —R^(b)X³R²⁰ (wherein X³ represents —O—, C(O)—S—, —SO—, —SO₂—,    —OC(O)—, —NR²¹C(O)_(s)—, —C(O)NR²²—, —SO₂NR²³, —NR²⁴SO₂— or —NR²⁵—    (wherein R²¹, R²², R²³, R²⁴ and R²⁵ each independently represents    hydrogen, C₁₋₃alkyl, hydroxy C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl and s    is 1 or 2) and R²⁰ represents hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or a    5-6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which C₁₋₆alkyl group may    bear 1, 2 or 3 substituents selected from oxo, hydroxy, halogeno,    cyclopropyl, amino, C₁₋₄alkylamino, C₁₋₄alkanoyldi-C₁₋₄alkylamino,    C₁₋₄alkylthio, C₁₋₄alkoxy and which cyclic group may bear 1 or 2    substituents selected from oxo, hydroxy, halogeno, cyano,    C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,    C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group —(—O—)_(f)(R^(b′))_(g)D    (wherein f is 0 or 1, g is 0 or 1 and D is a cyclic group selected    from C₃₋₆cycloalkyl group, an aryl group or a 5-6-membered saturated    heterocyclic group with 1-2 heteroatoms, selected independently from    O, S and N, which cyclic group may bear one or more substituents    selected from halo or C₁₋₄alkyl));-   4) —R^(c)X⁴R^(c′)X⁵R²⁶ (wherein X⁴ and X⁵ which may be the same or    different are each —O—, C(O), —S—, —SO—, —SO₂—, —NR²⁷C(O)_(s)—,    —C(O)_(x)NR²⁸—, —SO₂NR²⁹—, —NR³⁰SO₂— or —NR³¹— (wherein R²⁷, R²⁸,    R²⁹, R³⁰ and R³¹ each independently represents hydrogen, C₁₋₃alkyl    or C₁₋₃alkoxyC₂₋₃alkyl and s is 1 or 2) and R²⁶ represents hydrogen,    C₁₋₃alkyl,hydroxyC₁₋₃alkylorC₁₋₃alkoxyC₂₋₃alkyl);-   5) R³² (wherein R³² is a 4-6-membered cycloalkyl or saturated    heterocyclic ring (linked via carbon or nitrogen) with 1-2    heteroatoms, selected independently from O, S and N, which    cycloalkyl or heterocyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄alkyl,    hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, cyclopropyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, carboxamido,    C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,    C₁₋₄alkylaminoC₁₋₄alkyl, C₁₋₄alkanoyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,    C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy nitro, amino,    C₁₋₄alkoxy, C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl,    —C(O)NR³⁸R³⁹, —NR⁴⁰C(O)R⁴¹ (wherein R³⁸, R³⁹, R⁴⁰ and R⁴¹, which may    be the same or different, each represents hydrogen, C₁₋₄alkyl,    hydroxyC₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    D is a cyclic group selected from C₃₋₆cycloalkyl, aryl or    5-6-membered saturated or unsaturated heterocyclic group with 1-2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from halo and    C₁₋₄alkyl);-   6) —R^(d)R³² (wherein R³² is as defined hereinbefore);-   7) —R^(e)R³² (wherein R³² is as defined hereinbefore);-   8) —R^(f)R³² (wherein R³² is as defined hereinbefore);-   9) R³³ (wherein R³³ represents a pyridone group, a phenyl group or a    5-6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1-3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents selected from hydroxy, nitro, halogeno, amino,    C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, oxo, cyanoC₁₋₄alkyl, cyclopropyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, di(C₁₋₄alkyl)amino,    C₁₋₄alkylaminoC₁₋₄alkyl, C₁₋₄alkanoyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,    C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy, carboxy,    carboxamido, trifluoromethyl, cyano, —C(O)NR³⁸R³⁹, —NR⁴⁰C(O)R⁴¹    (wherein R³⁸, R³⁹, R⁴⁰ and R⁴¹, which may be the same or different,    each represents hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD    (wherein f is 0 or 1, g is 0 or 1 and ring D is a cyclic group    selected from C₃₋₆cycloalkyl, aryl or 5-6-membered saturated or    unsaturated heterocyclic group with 1-2 heteroatoms, selected    independently from O, S and N, which cyclic group may bear one or    more substituents selected from halo and C₁₋₄alkyl);-   10) —R^(g)R³³ (wherein R³³ is as defined hereinbefore);-   11) —R^(h)R³³ (wherein R³³ is as defined hereinbefore);-   12) —R^(i)R³³ (wherein R³³ is as defined hereinbefore);-   13) —R^(j)X⁶R³³ (wherein X⁶ represents —O—, _C(O)—, —S—, —SO—,    —SO₂—, —OC(O)—, —NR³⁸C(O)—, —C(O)NR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or    —NR⁴²— (wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² each independently    represents hydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore);-   14) —R^(k)X⁷R³³ (wherein X⁷ represents —O—, C(O), —S—, —SO—,    —SO₂—NR⁴³C(O)—, —C(O)NR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷— (wherein    R⁴³, R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ each independently represents hydrogen,    C₁₋₃alkyl, hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as    defined hereinbefore);-   15) —R^(m)X⁸R³³ (wherein X⁸ represents —O—, —C(O)—, —S—, —SO—,    —SO₂—, —NR⁴⁸C(O)—, —C(O)NR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or NR⁵²—    (wherein R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹ and R⁵² each independently represents    hydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    R³³ is as defined hereinbefore);-   16) —R^(n)X⁹R^(n′)R³³ (wherein X⁹ represents —O—, —C(O)—, —S—, —SO—,    —SO₂—, —NR⁵³C(O)—, —C(O)NR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or —NR⁵⁷—    (wherein R⁵³, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ each independently represents    hydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    R³³ is as defined hereinbefore);-   17) —R^(p)X⁹—R^(p1)1R³² (wherein X⁹ and R³² are as defined    hereinbefore);-   18) C₂₋₅alkenyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   19) C₂₋₅alkynyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro,    amino, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino, aminosulphonyl,    N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;-   20) —R^(t)X⁹R^(t′)R³² (wherein X⁹ and R³² are as defined    hereinbefore);-   21) —R^(u)X⁹R^(u′)R³² (wherein X⁹ and R³² are as defined    hereinbefore); and-   22) —R^(v)R⁵⁸(R^(v′))_(q)(X⁹)_(r)R⁵⁹(wherein X⁹ is as defined    hereinbefore, q is 0 or 1, r is 0 or 1 and R⁵⁸ is a C₁₋₃alkylene    group or a cyclic group selected from cyclopropyl, cyclobutyl,    cyclopentylene, cyclohexylene or a 5-6-membered saturated    heterocyclic group with 1-2 heteroatoms, selected independently from    O, S and N, which C₁₋₃alkylene group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic    group may bear 1 or 2 substituents selected from oxo, hydroxy,    halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,    C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino,    di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D is a cyclic group selected from C₃₋₆cycloalkyl, aryl or    5-6-membered saturated or unsaturated heterocyclic group with 1-2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from halo and    C₁₋₄alkyl);and R⁵⁹ is hydrogen, C₁₋₃alkyl, or a cyclic group    selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and a    5-6-membered saturated heterocyclic group with 1-2 heteroatoms,    selected independently from O, S and N, which C₁₋₃alkyl group may    bear 1 or 2 substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkoxy and which cyclic group may bear 1 or 2 substituents    selected from oxo, hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,    C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl,    C₁₋₄alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄alkylaminoC₁₋₄alkyl,    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, C₁₋₄alkylaminoC₁₋₄alkoxy,    di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group    —(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 and    ring D, is a cyclic group selected from C₃₋₆cycloalkyl, aryl or    5-6-membered saturated or unsaturated heterocyclic group with 1-2    heteroatoms, selected independently from O, S and N, which cyclic    group may bear one or more substituents selected from halo and    C₁₋₄alkyl);-   and wherein R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(g),    R^(j), R^(n), R^(n′), R^(p), R^(p′), R^(t′), R^(u′), R^(v) and    R^(v′) are independently selected from C₁₋₈alkylene groups    optionally substituted by one or more substituents selected from    hydroxy, halogeno, amino,-   R^(e)R^(h), R^(k) and R^(t) are independently selected from    C₂₋₈alkenylene groups optionally substituted by one or more    substituents selected from hydroxy, halogeno, amino, and R^(u) may    additionally be a bond; and-   R^(f), R^(n), R^(m) and R^(u) are independently selected from by    C₂₋₈alkynylene groups optionally substituted by one or more    substituents selected from hydroxy, halogeno, amino.

For instance, R¹, R², R³, R⁴ are independently selected from, halo,cyano, nitro, trifluoromethyl, C₁₋₃alkyl, —NR⁷R⁸ (wherein R⁷ and R⁸,which may be the same or different, each represents hydrogen orC₁₋₃alkyl), or other groups from formula —X¹R⁹ (wherein X¹ represents adirect bond, —O—, —CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—, —NR¹⁰CO—,—CONR¹¹—, —SO₂NR¹²—, —NR¹³SO₂— or —NR¹⁴— (wherein R¹⁰, R¹¹, R¹², R¹³ andR¹⁴ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl), and R⁹ is selected from one of the followinggroups:

-   1′) hydrogen or C₁₋₅alkyl which may be unsubstituted or which may be    substituted with one or more groups selected from hydroxy, fluoro or    amino,-   2′) C₁₋₅alkylX²C(O)R¹⁵ (wherein X² represents —O— or —NR¹⁶— (in    which R¹⁵ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and    R⁵ represents C₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹ (wherein R¹⁷, R¹⁸ and R¹⁹    which may be the same or different each represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   3′) C₁₋₅alkylX³R²⁰ (wherein X³ represents —O—, —S—, —SO—, —SO₂—,    —OCO—, —NR²¹CO—, —CONR²²—, —SO₂NR²³—, —NR²⁴SO₂— or —NR²⁵— (wherein    R²¹, R²², R²³, R²⁴ and R²⁵ each represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²⁰ represents hydrogen, C₁₋₃alkyl,    cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic    group with 1-2 heteroatoms, selected independently from O, S and N,    which C₁₋₃alkyl group may bear 1 or 2 substituents selected from    oxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group may    bear 1 or 2substituents selected from oxo, hydroxy, halogeno,    C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);-   4′) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²⁶ (wherein X⁴ and X⁵ which may be the    same or different are each —O—, —S—, —SO—, —SO₂—, —NR²⁷CO—,    —CONR²⁸—, —SO₂NR²⁹—, —NR³⁰SO₂— or —NR³¹— (wherein R²⁷, R²⁸, R²⁹, R³⁰    and R³¹ each independently represents hydrogen, C₁₋₃alkyl or    C₁₋₃alkoxyC₂₋₃alkyl) and R²⁶ represents hydrogen or C₁₋₃alkyl);-   5′) R³² (wherein R³² is a 5-6-membered saturated heterocyclic group    (linked via carbon or nitrogen) with 1-2 heteroatoms, selected    independently from O, S and N, which heterocyclic group may bear 1    or 2 substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,    C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl and    C₁₋₄alkylsulphonylC₁₋₄alkyl);-   6′) C₁₋₅alkylR³² (wherein R³² is as defined in (5′) above);-   7′) C₂₋₅alkenylR³² (wherein R³² is as defined in (5′) above);-   8′) C₂₋₅alkynylR³² (wherein R³² is as defined in (5′) above);-   9′) R³³ (wherein R³³ represents a pyridone group, a phenyl group or    a 5-6-membered aromatic heterocyclic group (linked via carbon or    nitrogen) with 1-3 heteroatoms selected from O, N and S, which    pyridone, phenyl or aromatic heterocyclic group may carry up to 5    substituents on an available carbon atom selected from hydroxy,    halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,    C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,    trifluoromethyl, cyano, —CONR³⁴R³⁵ and —NR³⁶COR³⁷ (wherein R³⁴, R³⁵,    R³⁶ and R³⁷, which may be the same or different, each represents    hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));-   10′) C₁₋₅alkylR³³ (wherein R³³ is as defined in (9′) above);-   11′) C₂₋₅alkenylR³³ (wherein R³³ is as defined in (9′) above);-   12′) C₂₋₅alkynylR³³ (wherein R³³ is as defined in (9′) above);-   13′) C₁₋₅alkylX⁶R³³ (wherein X⁶ represents —O—, —S—, —SO—, —SO₂—,    —NR³⁸CO—, —CONR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸,    R³⁹, R⁴⁰, R⁴¹ and R⁴² each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined    hereinbefore);-   14′) C₂₋₅alkenylX⁷R³³ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴³CO—, —CONR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷— (wherein R⁴³,    R⁴⁴, R⁴⁵, R⁴⁶ and R⁴⁷ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined    hereinbefore);-   15′) C₂₋₅alkynylX⁸R³³ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—,    —NR⁴⁸CO—, —C(O)NR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or —NR⁵²— (wherein R⁴⁸,    R⁴⁹, R⁵⁰, R⁵¹ and R⁵² each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined    hereinbefore);-   16′) C₁₋₃alkylX⁹C₁₋₃alkylR³³ (wherein X⁹ represents —O—, —S—, —SO—,    —SO₂—, —NR⁵³CO—, —C(O)NR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or —NR⁵⁷— (wherein    R⁵³, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ each independently represents hydrogen,    C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined    hereinbefore); and-   17′) C₁₋₃alkylX⁹C₁₋₃alkylR³² (wherein X⁹ and R³² are as defined in    (5′) above); provided that least one of R² or R³ is other than    hydrogen.

Preferably R¹ is hydrogen. Suitably R⁴ is hydrogen or a smallsubstituent such as halo, C₁₋₄ alkyl or C₁₋₄alkoxy such as methoxy.

Preferably both R¹ and R⁴ are hydrogen.

In a preferred embodiment, at least one group R² or R³, preferably R³,comprises a chain of at least 3 and preferably at least 4 optionallysubstituted carbon atoms or heteroatoms such as oxygen, nitrogen orsulphur. Most preferably the chain is substituted by a polar group whichassists in solubility.

Suitably R³ is a group X¹R⁹.

Preferably in this case, X¹ is oxygen and R⁹ includes a methylene groupdirectly adjacent X¹. Preferably where bridging alkylene, alkenylene oralkynylene groups R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(g),R^(j), R^(n), R^(n′), R^(p), R^(p′), R^(t′), R^(u′), R^(v), R^(v′),R^(e)R^(h), R^(k)R^(t), R^(f), R^(i), R^(m) and R^(u) are present, atleast one such group includes a substituent and in particular a hydroxysubstituent.

In particular R⁹ is selected from a group of formula (1), (3), (6) or(10) above and preferably selected from groups (1) or (10) above.Particular groups R⁹ are those in group (1) above, especially alkyl suchas methyl or halo substituted alkyl, or those in group (10) above. Inone suitable embodiment, at least one of R² or R³ is a groupOC₁₋₅alkylR³³ and R³³ is a heterocyclic ring such as an N-linkedmorpholine ring such as 3-morpholinopropoxy.

Other preferred groups for R³ are groups of formula (3) above inparticular those where X³ is NR²⁵.

Suitably R² is selected from, halo, cyano, nitro, trifluoromethyl,C₁₋₃alkyl, —NR⁷R⁸ (wherein R⁷ and R⁸, which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl), or a group —X¹R⁹.Preferred examples of —X¹R⁹ for R² include those listed above inrelation to R³.

Other examples for R² and R³ include methoxy or 3,3,3-trifluoroethoxy.

Suitably R⁵ is optionally substituted pyridine or optionally substitutedpyrimidine and is preferably optionally substituted pyrimidine.

Most preferably, R⁵ is a substituted pyridine or substituted pyrimidinegroup. Suitably, at least one substituent is positioned at the paraposition on the ring R⁵. Thus suitable groups R⁵ include compounds ofsub-formulae Most preferably, R⁵ is a substituted pyridine orsubstituted pyrimidine group. Suitably, at least one substituent ispositioned at the para position on the ring R⁵. Thus suitable groups R⁵include compounds of sub-formulae

wherein R⁸⁰ is a substituent group and in particular R⁸⁰ is a largesubstituent of a chain of at least 4 atoms, in particular a group ofsub-formula (II), (f) or sub-formula (VI) as defined below, and R⁸¹ ishydrogen or a substituent and in particular a small substituent such ashalo, C₁₋₄alkoxy such as methoxy, or othoxy, cyano or trifluoromethyl,or phenyl;

Suitable substituents for the pyridine or pyrimidine groups R⁵ include afunctional group as defined above; hydrocarbyl optionally substituted byone or more functional groups as defined above; heterocyclyl optionallysubstituted by one or more functional groups or hydrocarbyl groupswherein the hydrocarbyl group may be substituted by a functional groupor a heterocyclic group as defined above; alkoxy optionally substitutedby a functional group, or a heterocylic group which is optionallysubstituted by a functional group.

In particular, R⁵ is substituted by one or more groups selected fromhalo,C₁₋₄alkyl, optionally substituted C₁₋₆ alkoxy, C₁₋₄alkoxymethyl,di(C₁₋₄alkoxy)methyl, C₁₋₄alkanoyl, trifluoromethyl, cyano, amino,C₂₋₅-alkenyl, C₂₋₅alkynyl, a phenyl group, a benzyl group or a5-6-membered heterocyclic group with 1-3 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may be aromaticor non-aromatic and may be saturated (linked via a ring carbon ornitrogen atom) or unsaturated (linked via a ring carbon atom), and whichphenyl, benzyl or heterocyclic group may bear on one or more ring carbonatoms up to 5 substituents selected from hydroxy, halogeno, C₁₋₃alkyl,C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl, cyano, amino, nitro,C₂₋₄alkanoyl, C₁₋₄alkanoylamino, C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl,C₁₋₄alkylsulphinyl, C₁₋₄alkylsulphonyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,N,N-di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkylsulphonylamino, and asaturated heterocyclic group selected from morpholino, thiomorpholino,pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl,which saturated heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl.

Other substituents groups for R⁵ include carboxamido, carboxy andbenzoyl.

Suitably R⁵ is substituted with at least one group which has at least 4atoms which may be carbon or heteroatoms forming a chain. A particularexample of such a substituent is optionally substituted alkoxy. Suitablesubstituents for the alkoxy group include those listed above in relationto R⁷⁷, R⁷⁸ and R⁷⁹.

A further particular substituent group for R⁵ is a group of sub-formula(II)

-   where q′ is 0, 1, 2, 3 or 4;-   s′ is 0or 1;-   X¹² is C(O) or S(O₂), and preferably C(O);-   R⁷⁰ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino,    N—C₁₋₆alkylamino,-   N,N-(C₁₋₆alkyl)₂amino, hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy,    aminoC₂₋₆alkoxy,-   N—C₁₋₆alkylaminoC₂₋₆alkoxy, N,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy or    C₃₋₇cycloalkyl,-   or R⁷⁰ is of the Formula (III):    -K-J  (III)-   wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy,    imino, N—(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene, iminoC₁₋₆alkylene,    N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—, —NHSO₂— or    —NHC(O)—C₁₋₆alkylene-,-   and any aryl, heteroaryl or heterocyclyl group in a R⁷⁰ group may be    optionally substituted by one or more groups selected from hydroxy,    halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,    carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₁₋₆alkoxy, —O—(C₁₋₃alkyl)—O—, C₁₋₆alkylS(O)_(n)— (wherein n is    0-2), N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,    N—C₁₋₆alkylcarbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,    C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,    N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino and    C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, and suitably also oxo,-   or any aryl, heteroaryl or heterocyclyl group in a R⁷⁰ group may be    optionally substituted with one or more groups of the Formula (IV):    -B¹-(CH₂)_(p)-A¹  (IV)-   wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano, amino,    N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, carboxy,    C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl or    N,N-(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B¹ is a bond, oxy, imino,    N—(C₁₋₆alkyl)imino or —NHC(O)—, with the proviso that p is 2 or more    unless B¹ is a bond or —NHC(O)—;-   or any aryl, heteroaryl or heterocyclyl group in a R⁷⁰ group may be    optionally substituted with one or more groups of the Formula (V):    -E¹-D¹  (V)-   wherein D¹ is aryl, heteroaryl or heterocyclyl and E¹ is a bond,    C₁₋₆alkylene, oxyC₁₋₆alkylene, oxy, imino, N—(C₁₋₆alkyl)imino,    iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene,    C₁₋₆alkylene-oxyC₁₋₆alkylene, C₁₋₆alkylene-iminoC₁₋₆alkylene,    C₁₋₆alkylene-N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—,    —SO₂NH— or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or    heterocyclyl group in a substituent on R⁴ may be optionally    substituted with one or more groups selected from hydroxy, halo,    C₁₋₆alkyl, C₁₋₆alkoxy, carboxy, C₁₋₆alkoxycarbonyl, carbamoyl,    N—C₁₋₆alkylcarbamoyl, N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino,    N—C₁₋₆alkylamino and N,N-(C₁₋₆alkyl)₂amino, and any C₃₋₇cycloalkyl    or heterocyclyl group in a R⁷⁰ group may be optionally substituted    with one or two oxo or thioxo substituents, and any of the R⁷⁰    groups defined hereinbefore which comprises a CH₂ group which is    attached to 2 carbon atoms or a CH₃ group which is attached to a    carbon atom may optionally bear on each said CH₂ or CH₃ group a    substituent selected from hydroxy, amino, C₁₋₆alkoxy,    N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino and heterocyclyl;-   and R⁹⁹ is hydrogen or a group C(O)R⁷⁰ where R⁷⁰ is as defined above    and is preferably hydrogen.

In yet a further alternative, R⁷⁰ may be cycloalkenyl or cycloalkynylsuch as cyclohexenyl, alkenyl optionally substituted by aryl such asstyryl or alkyl substituted by cycloalkenyl such as cyclohexenylethyl

Suitably, when q′ is 0, R⁷⁰ is other than hydroxy.

Preferably s′ is 0.

Preferably the group of sub-formula (II) is a group of sub-formula (IIA)

-   where s′, q′ and R⁷⁰ are as defined above.

A preferred example of a substituent of formula (II) or (IIA) is a groupwhere q′ is 0.

Examples of heterocyclyl groups for R⁷⁰ include pyridyl,methyledioxyphenyl, furyl, pyrrolyl, thiophene, quinolyl, isoquinolyl,thiazolyl, thiadiazolyl, pyrazolyl, tetrahydrothiophene-1,1-dioxide,dioxan, tetrahydrofuryl, pyrazinyl, imidazolyl, tetrahydropyran,indolyl, indanyl, pyrrolidine, or isoxazolyl.

A particular example of a group R⁷⁰ in formula (II) is phenyl.Preferably R⁷⁰ is halosubstituted phenyl and 2-chloro4-fluorophenyl is aparticularly preferred example.

More suitably R⁵ is substituted by a group —X¹⁰(CH₂)_(p′)—X¹¹R¹⁰⁰ or—X¹³R¹⁰⁰ where p′ is 1-3, X¹⁰ and X¹¹ are independently selected from abond, —O—, —S— or NR¹⁰¹—where R¹⁰¹ is hydrogen or a C₁₋₃alkyl, providedthat one of X¹⁰ or X¹¹ is a bond; X¹³ is —O—, —S— or NR¹⁰²— where R¹⁰²is hydrogen or a C₁₋₄alkyl and R¹⁰⁰ is hydrogen or optionallysubstituted hydrocarbyl or optionally substituted heterocycyl. Suitableoptional substituents for hydrocarbyl and heterocyclyl groups R¹⁰⁰include functional groups as defined above. Preferred groups R¹⁰⁰ arehydrocarbyl or heterocyclyl groups which are included in the definitionof R⁷⁰ as defined hereinbefore. Preferably one of X¹⁰ or X¹¹ is otherthan a bond.

Particular examples of R⁷⁰ in this instance include optionallysubstituted phenyl and especially, mono or di-halophenyl,or optionallysubstituted pyridyl such as nitropyridyl.

Another preferred substituent group for R⁵ is a group of formula (VI)

where R⁷¹ and R⁷² are independently selected from hydrogen or C₁₋₄alkyl,or R⁷¹ and R⁷² together form a bond, and R⁷³ is a group OR⁷⁴, NR⁷⁵R⁷⁶where R⁷⁴, R⁷⁵ and R⁷⁶ are independently selected from optionallysubstituted hydrocarbyl or optionally substituted heterocyclic groups,and R⁷⁵ and R⁷⁶ may additionally form together with the nitrogen atom towhich they are attached, an aromatic or non-aromatic heterocyclic ringwhich may contain further heteroatoms.

Suitable optional substituents for hydrocarbyl or heterocyclic groupsR⁷⁴, R⁷⁵ and R⁷⁶ include functional groups as defined above.Heterocyclic groups R⁷⁴, R⁷⁵ and R⁷⁶ may further be substituted byhydrocarbyl groups.

In particular, R⁷¹ and R⁷² in sub-formula (VI) are hydrogen.

Particular examples of R⁷³ are groups OR⁷⁴ where R⁷⁴ is C₁₋₄alkyl.

Further examples of R⁷³ are groups of formula NR⁷⁷R⁷⁶ where one of R⁷⁵or R⁷⁶ is hydrogen and the other is optionally substituted C₁₋₆alkyl,optionally substituted aryl or optionally substituted heterocyclyl.

In particular, one of R⁷⁵ or R⁷⁶ is hydrogen and the other is C₁₋₆alkyloptionally substituted with trifluoromethyl, C₁₋₃ alkoxy such asmethoxy, cyano, thioC₁₋₄alkyl such as methylthio, or heterocyclyloptionally substituted with hydrocarbyl, such as indane, furanoptionally substituted with C₁₋₄ alkyl such as methyl.

In another embodiment, one of R⁷⁵ or R⁷⁶ is hydrogen and the other is anoptionally substituted heterocyclic group such as pyridine, or a phenylgroup optionally substituted with for example one or more groupsselected from halo, nitro, alkyl such as methyl, or alkoxy such asmethoxy.

Other suitable substituents groups for R⁵ are groups of sub-formula(VII)

where p″ is 0 or 1 and R⁸³ and R⁸⁴ are independently selected fromhydrogen, optionally substituted hydrocarbyl or optionally substitutedheterocyclyl, or R⁸³ and R⁸⁴ together with the nitrogen atom to whichthey are attached form an optionally substituted heterocyclic ring.Suitable optional substituents for hydrocarbyl or heterocyclic groupsR⁸³ and R⁸⁴ include functional groups as defined above and heterocyclicgroups R⁸³ or R⁸⁴ may further be substituted by a hydrocarbyl group.

Examples of groups for R⁸³ and R⁸⁴ include C₁₋₄alkyl substituted bycycloalkyl such as 2-cyclopropylethyl; C₁₋₆alkylthio such a methylthio;C₁₋₆alkoxy; or a group —(CH₂)_(q)R⁷⁰ where q and R⁷⁰ are as definedabove in relation to formula (II).

Suitably one of R⁸³ or R⁸⁴ is hydrogen, or methyl, ethyl or propyloptionally substituted with hydroxy and preferably one of R⁸³ or R⁸⁴ ishydrogen. In this case, the other is suitably a larger substituent forexample of at least 4 carbon or heteroatoms, and is optionallysubstituted hydrocarbyl or optionally substituted heterocyclyl.Particular optionally substituted hydrocarbyl groups for R⁸³ or R⁸⁴include alkyl, cycloalkyl, alkenyl, or aryl any of which is optionallysubstituted with a functional group as defined above, or in the case ofaryl groups, with an alkyl group and in the case of alkyl group, with anaryl or heterocyclic group either of which may themselves be optionallysubstituted with alkyl or a functional group. Examples of optionallysubstituted aryl groups R⁸³ or R⁸⁴ include phenyl optionally substitutedwith one or more groups selected from C₁₋₆ alkyl group such as methyl orethyl (either of which may be optionally substituted with a functionalgroup such as hydroxy); or a functional group as defined above (such ashalo like fluoro, chloro cr bromo, hydroxy, alkoxy such as methoxy,trifluoromethyl, nitro, cyano, trifluromethoxy, CONH₂, C(O)CH₃, amino,or dimethylamino).

When R⁸³ or R⁸⁴ is an optionally substituted alkyl group, it is suitablya C₁₋₆alkyl group, optionally substituted with one or more functionalgroups (such as cyano, hydroxy, alkoxy in particular methoxy or ethoxy,alkylthio in particular methylthio, COOalkyl such as COOCH₃), or aryloptionally substituted with a functional group as defined above (inparticular in relation to R⁸³ or R⁸⁴ themselves, or an optionallysubstituted heterocyclic group such as N-methyl pyrrole.

When R⁸³ and R⁸⁴ is optionally substituted cycloalkyl, it is suitablecyclohexyl optionally substituted with a functional group such ashydroxy.

When R⁸³ and R⁸⁴ is optionally substituted alkenyl, it is suitablyprop-2-enyl.

When R⁸³ or R⁸⁴ is optionally substituted heterocyclyl, or R⁸³ and R⁸⁴together form a heterocyclic group, then this may be aromatic ornon-aromatic and includes in particular, piperadine, piperazine,morpholino, pyrrolidine or pyridine any of which may be optionallysubstituted with a functional group such as hydroxy, alkoxy such asmethoxy, or alkyl such as methyl which may itself be substituted withfor instance a hydroxy group.

Where possible, the group R⁵ may have a second substituent in particularhalo, C₁₋₄alkoxy such as methoxy, or ethoxy, cyano, trifluoromethyl, orphenyl. Preferably any second substituent is a small group.

Most preferably, in the compound of formula (I), at least onesubstituent is positioned at the para position on the pyrimidine ring.Thus preferably the compound of formula (I) incorporates a further groupof sub-formulae (vi and vii):

wherein R^(x) is hydrogen, halo, C₁₋₄alkoxy, cyano, trifluoromethyl, orphenyl; Where R^(x) is other than hydrogen, it is preferably a smallgroup such as halo, chloro, flouro, methoxy, ethoxy cyano, ortrifloruomethyl;

-   Y is a group —NR⁶C(O)—, —C(O)NR⁶—, —NR⁶S(O)₂—, —NHR⁶—, —NR⁶CH═N—,    —C(═NR⁶)NR^(6′)—, —NR⁶C(═NR^(6′))NR^(6″)—, —C(O), —CH═CHC(O)NR⁶—,    —C≡CC(O)NR⁶, —CH═CH—, —C≡C—, —S—, —S(O)—, —S(O)₂—, or —O— where R⁶,    R^(6′) and R^(6″) are independently selected from hydrogen or    C₁₋₄alkyl.-   Preferably, Y is a group —NR⁶C(O)—, —C(O)NR⁶—, —NR⁶S(O)₂—, —NHR⁶—,    —NR⁶CH═N—, —C(═NR⁶)NR^(6″)—, —NR⁶C(═NR^(6′))NR^(6″)—,    —CH═CHC(O)NR⁶—, —C≡CC(O)NR⁶, —CH═CH—, —C≡C—, —S— or —S(O)—.-   Most preferably, Y is a group —NR⁶C(O)— or —C(O)NR⁶— and most    preferably Y is —NR⁶C(O)—.-   q is 0 or an integer of from 1 to 6;-   Suitably, when Y is C(O), —S(O)₂—, or —O—, either q is other than 0    or R⁷⁰ is other than unsubstituted phenyl.

R⁷⁰ is as defined in relation to Sub Formulae (iv) above.

Preferably, R⁵ is a group of sub-formula (vi) or (vii) as defined above,and most preferably is a group of sub-formula (vi).

A particular example of a compound of Formula (I) is a compound ofFormula (VIII)

Wherein R¹, R², R³, R⁴, R^(x), Y, q and R⁷⁰ are as defined above.

A particular example of a compound of formula (I) is a compound offormula (IX)

where R¹, R², R³ and R⁴ are as defined above and R^(y) is hydrogen orhalogen.

Suitable pharmaceutically acceptable salts of compounds of formula (I)include acid addition salts such as methanesulfonate, fumarate,hydrochloride, hydrobromide, citrate, maleate and salts formed withphosphoric and sulphuric acid. There may be more than one cation oranion depending on the number of charged functions and the valency ofthe cations or anions. Where the compound of formula (I) includes anacid functionality, salts may be base salts such as an alkali metal saltfor example sodium, an alkaline earth metal salt for example calcium ormagnesium, an organic amine salt for example triethylamine, morpholine,N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine,N,N-dibenzylethylamine or amino acids for example lysine. A preferredpharmaceutically acceptable salt is a sodium salt.

An in vivo hydrolyzable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkyl esters such as methyl or ethyl esters, C₁₋₆alkoxymethyl estersfor example methoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxy-carbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl;

-   1,3-dioxolen-2-onylmethyl esters for example    5-methyl-1,3-dioxolen-2-onylmethyl; and-   C₁₋₆alkoxycarbonyloxyethyl esters for example    1-methoxycarbonyloxyethyl and may be formed at any carboxy group in    the compounds of this invention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl.

Suitable amides are derived from compounds of formula (I) which have acarboxy group which is derivatised into an amide such as a N—C₁₋₆alkyland N,N-di-(C₁₋₆alkyl)amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethylamide.

Esters which are not in vivo hydrolysable may be useful as intermediatesin the production of the compounds of formula (I).

Particular examples of compounds of formula (I) are set out in Table 1

TABLE I

Compound No. R¹ R² R³ 1 H CN

2 H OCH₃

3 H H

4 H H

5 H H OCH₂CH₂OCH₃ 6 H H OCH₂CH₂OCH₂CH₂OCH₃ 7 H NHCOCH₃ H 8 Cl H H 9 H CNH 10 CH₃ H CH₃ 11 H H Cl 12 H H H 13 H H CF₃ 14 H CF₃ H

Compounds of formula (I) may be prepared by various methods which wouldbe apparent from the literature. For example compounds of formula (I)may be prepared by reacting a compound of formula (X)

where R¹, R², R³, and R⁴ are as defined in relation to formula (I) andR⁸⁵ is a leaving group, with a compound of formula (XI)

where R^(a), Y, q and R⁷⁰ are as defined in relation to formula (I).Suitable leaving groups for R⁸⁵ include halo such as chloro, mesylateand tosylate. The reaction is suitably effected in an organic solventsuch as an alcohol like pentanol or isopropanol, at elevatedtemperatures, conveniently at the reflux temperature of the solvent.

Compounds of formula (X) and (XI) are either known compounds or they canbe derived from known compounds by conventional methods.

Compounds of formula (XI) may be prepared by reduction of a compound offormula (XII)

for example by reaction with hydrogen in the presence of a catalyst suchas a platinum or palladium catalyst or by reaction with a reducing agentsuch as sodium hydrosulphite.

Compounds of formula (XII) can for example, be derived from compounds offormula (XIII)

where R^(x) is as defined hereinbefore and R^(y) is amino, carboxy,halo, alkylketone, aldehyde, nitrile, mercapto, or hydroxy using routesset out in the literature. For example, where Y is —NR⁶C(O)— or—NR⁶S(O)₂—, the compound of formula (XII) can be derived from compoundsof formula (XIV)

where R^(x) and R⁶ are as defined in relation to formula (I), byreaction with a compound of formula (XV)

where q and R⁷⁰ are as defined in relation to formula (I), Z is a bond,C(O) or S(O), and R⁸⁸ is a leaving group such as halo or aryloxy. Thereaction is suitably effected in the presence of a base such as pyridineat elevated temperatures, conveniently at the reflux temperature of thesolvent.

Similarly, compounds of formula (XII) where Y is —C(O)NR⁶— may beprepared from compound of formula (XVI)

where R^(x) is as defined in relation to formula (I), using conventionalamidation methods with the appropriate amine. Compounds of formula (XVI)are either known compounds or they may be prepared by hydrolysis ofcompounds of formula (XVII)

where R^(x) is as defined above.

Compounds of formula (XII) where Y is an acetylene group of formula—C≡C— may be prepared by reduction of the nitrile of formula (XVII) forexample, with di-isobutylaluminium hydride to give the correspondingaldehyde, which can then be reacted for example with phosphorus ylidswould give compounds of formula (XII) where Y is —C≡C—. Reaction ofnitrile (XVII) with alkyl- or aryl lithiums would give ketones offormula (XII) where Y═C(O)—.

Nitriles of formula (XVII) can be made from a compound of formula (XIII)where R^(y) is a sulphide by oxidation with a peracid such asmeta-chlorobezoic acid to form the corresponding sulphone and reactionof this product with potassium cyanide in a solvent such asN-methylpyrrolidine.

Where in the compound of formula (X), a substitutent such as R³ is aparticularly complex substituent, it may be introduced by reacting acompound of formula (XIII)

where R¹ and R⁴ are as defined in relation to formula (I), R⁸⁵ is asdefined in relation to formula (X), one of R^(2′) or R^(3′) isequivalent to R² or R³ as defined in relation to formula (I), and theother is hydroxy; with a compound of formula (XVIII) H—X—R⁹  (XIX)where X is as defined in relation to formula (I) and is preferablyoxygen, and R⁹ is as defined in relation to formula (I). The reaction issuitably effected in the presence of dehydrating reagents such asdiethyl azodicarboxylate and triphenylphosphine. It is carried out infor example, an organic such as dichloromethane, preferably at moderatetemperatures, for example of from 0 to 50° C. and conveniently atambient temperature.

Compounds of formula (I) are inhibitors of aurora 2 kinase. As a result,these compounds can be used to treat disease mediated by these agents,in particular proliferative disease.

According to a further aspect of the invention there is provided acompound of the formula (I) as defined herein, or a pharmaceuticallyacceptable salt or an in vivo hydrolysable ester thereof, for use in amethod of treatment of the human or animal body by therapy. Inparticular, the compounds are used in methods of treatment ofproliferative disease such as cancer and in particular cancers such ascolorectal or breast cancer where aurora 2 is upregulated.

According to a further aspect of the present invention there is provideda method for inhibiting aurora 2 kinase in a warm blooded animal, suchas man, in need of such treatment, which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, or an in vivo hydrolysable esterthereof.

The invention also provides a pharmaceutical composition comprising acompound of formula (I) as defined herein, or a pharmaceuticallyacceptable salt, or an in vivo hydrolysable ester thereof, incombination with at pharmaceutically acceptable carrier. Preferredcompounds of formula (I) for use in the compositions of the inventionare as described above.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal track, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring-agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedure well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30μ or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on Formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine. As mentioned above, compounds of the Formula I are useful intreating diseases or medical conditions which are due alone or in partto the effects of aurora 2 kinase.

In using a compound of the Formula I for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 0.5 mg to30 mg per kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 0.5 mgto 25 mg per kg body weight will be used. Oral administration is howeverpreferred.

A further aspect of the invention comprises a compound of formula (I) asdefined above, or a pharmaceutically acceptable salt or in vivohydrolysable ester thereof, for use in the preparation of a medicamentfor the treatment of proliferative disease. Preferred compounds offormula (I) for this purpose are as described above.

The following Examples illustrate the invention.

EXAMPLE 1

Preparation of Compound No. 1 in Table 1

Hydrochloric acid (0.05 ml of a 6.2 N solution in isopropanol) was addedto a solution of 4-chloro-6-cyano-7-(3-morpholinopropoxy)quinoline (110mg, 0.33 mmol) and 2-(N-benzoyl)2,5-diaminopyrimidine (85 mg, 0.40 mmol)in 2-pentanol (5 ml) and the mixture heated, at 120° C. for 6 hours. Thereaction mixture was cooled to ambient temperature, diluted with ethylacetate (25 ml), and the solid which precipitated was collected bysuction filtration and washed with ethyl acetate. Purification by flashchromatography on silica gel, eluting with 5-20% methanol indichloromethane yielded the title compound (100 mg, 59%) as a whitesolid:

¹H NMR (DMSOd₆, trifluoroacetic acid) 9.28 (s, 1H), 8.90 (s, 2H), 8.62(d, 1H), 8.01 (d, 2H), 7.60 (m, 2H), 7.52 (t, 2H), 7.01 (d, 1H), 4.41(m, 2H), 4.01 (d, 2H), 3.75 (t, 2H), 3.54 (d, 2H), 3.35 (t, 2H), 3.16(t, 2H), 2.48 (m, 2H): MS (−ve ESI): 510 (M−H)⁻.

4-Chloro-6-cyano-7-(3-morpholinopropoxy)quinoline and 2-(N-benzoyl)2,5-diaminopyrimidine, used as the starting materials, were obtained asfollows:

a) A mixture of 4-chloro-6-cyano-7-hydroxyquinoline (0.82 g, 4.0 mmol)in dichloromethane (25 ml) and N-(3-hydroxypropyl)morpholine (0.88 g,6.0 mmol) was treated with diethyl azodicarboxylate (1.58 ml, 8.0 mmol)and triphenylphosphine (2.1 g, 8.0 mmol) for 1 hour at ambienttemperature. Purification of the crude product by flash chromatographyon silica gel, eluting with 5-10% methanol in 1:1 ethylacetate/dichloromethane yielded the title compound (1.10 g, 69%) as awhite solid:

¹H-NMR (DMSOd₆): 8.89 (d, 1H), 8.66 (s, 1H), 7.72 (d, 1H), 7.69 (s, 1H),4.35 (t, 2H), 3.58 (m, 4H), 2.51 (t, 2H), 2.38 (m, 4H), 2.01 (m, 2H): MS(+ve ESI): 332 (M+H)⁺.

b) Benzoyl chloride (0.92 ml, 7.93 mmol) was added dropwise to a stirredsolution of 2-amino-5-nitropyrimidine (1.00 g, 7.14 mmol) in pyridine(20 ml) and the reaction was heated at reflux for 4 hours under an inertatmosphere. The reaction was allowed to cool to ambient temperature,poured into water (200 ml) and allowed to stand for 16 hours. The solidwas collected by suction filtration, washed with water (3×20 ml) anddried in vacuo. An oily residue on the surface of the aqueous phase wasdissolved in dichloromethane (50 ml) and then purified by flashchromatography on silica gel, eluting with 1-3% methanol. The twomaterials were identical and yielded 2-(N-benzoyl)2-amino-5-nitropyrimidine (826 mg, 47% yield) as a white solid:

¹H-NMR (DMSO d₆): 11.73 (s, 1H), 9.43 (s, 1H), 7.96 (d, 2H, J=8 Hz),7.47-7.65 (m, 3H): MS (+ve ESI): 243 (M−H)³⁰ , MS (+ve ESI): 245 (M+H)⁺.

c) 10% Platinum on carbon (71 mg, 0.036 mmol) was added to a solution2-(N-benzoyl) 2-amino-5-nitropyrimidine (733 mg, 3.00 mmol) in ethanol(100 ml) at ambient temperature and the reaction stirred for 1 hourunder an atmosphere of hydrogen. The reaction was filtered through a padof celite and the solvents were evaporated in vacuo. Purification byflash chromatography on silica gel, eluting with 5% methanol indichloromethane yielded 2-(N-benzoyl) 2,5-diaminopyrimidine (91 mg, 14%yield) as white solid:

¹H-NMR (DMSO d₆): 8.63 (s, 1H), 8.14 (s, 2H), 7.90 (d, 2H, J=8 Hz),7.42-7.56 (m, 3H), 3.76 (s, 1H): MS (+ve ESI): 213 (M+H)⁺, MS (+ve ESI):215 (M+H)⁻.

d) In an alternative procedure, a solution of 2-amino-5-nitropyrimidine(15.0 g, 107 mmol) and benzoic anhydride (48 g, 214 mmol) in diphenylether (53 g) was heated at 160° C. for 5 hours. The reaction was cooledto 90° C., t-butyl methyl ether (200 ml) was added and the reactionallowed to cool to ambient temperature. Collection of the solid bysuction filtration, followed by washing with diethyl ether and drying invacuo, yielded 2-(N-benzoyl) 2-amino-5-nitropyrimidine (22.4 g, 86%yield) as a white solid.Platinum dioxide (2.0 g of a 10% w/w slurry) was added to a solution of2-(N-benzoyl) 2-amino-5-nitropyrimidine (22.4 g, 92 mmol) in a mixtureof ethyl acetate (200 ml) and ethanol (200 ml) and the reaction stirredunder a hydrogen atmosphere (2 atmospheres pressure) for 2 hours atambient temperature. The reaction was purged, the catalyst was filteredoff and the solvents were removed in vacuo. Purification of the crudeproduct by flash chromatography on silica gel, eluting with 5-10%methanol in dichloromethane yielded the title compound (15.6 g, 80%) asa white solid.

EXAMPLE 2

Preparation of Compound No. 2 in Table 1

An analogous reaction to that described in example 1, but starting with4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline (112 mg, 0.33 mmol),yielded the title compound (72 mg, 42%) as a white solid after flashchromatography on silica gel, eluting with 5-20% methanol in 1:1 ethylacetate/dichloromethane:

¹H-NMR (DMSOd₆, trifluoroacetic acid): 8.94 (s, 2H), 8.48 (d, 1H), 8.16(s, 1H), 8.02 (d, 2H), 7.53 (m, 4H), 6.92 (d, 1H), 4.33 (t, 2H), 4.03(m, 5H), 3.78 (t, 2H), 3.55 (d, 2H) 3.35 (t, 2H), 3.17 (m, 2H), 2.49 (m,2H) MS (+ve ESI): 515 (M+H)⁺.

4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline, used as thestarting material, was obtained as follows:

A mixture of 4-chloro-6-methoxy-7-hydroxy quinoline (0.63 g, 3.0 mmol)and N(3-hydroxypropyl)morpholine (0.54 g, 3.8 mmol) was treated withdiethyl azodicarboxylate (1.38 g, 6.0 mmol) and triphenylphosphine (1.57g, 6.0 mmol) at room temperature for 2 hours. Purification by flashchromatography on silica gel, eluting with 0-20% methanol in 1:1 ethylacetate/dichloromethane yielded4-Chloro-6-methoxy-7-(3-morpholinopropoxy)-quinoline (0.70 g, 69% yield)as white solid:

¹H-NMR (DMSOd₆): 7.56 (d, 1H), 7.46 (s, 1H), 7.39 (s, 1H), 4.22 (t, 2H),4.02 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H).

EXAMPLE 3

Preparation of Compound 3 in Table 1

An analogous reaction to that described in example 1, but starting with4-chloro-7-(2-(1,2,4 triazolo)ethoxy)quinoline (110 mg, 0.40 mmol),yielded the title compound (130 mg, 72%) as a white solid after flashchromatography on silica gel, eluting with 5-15% methanol in 1:1 ethylacetate/dichloromethane:

¹H-NMR (DMSOd₆, TFA): 9.30 (s, 1H), 8.92 (s, 2H), 8.64 (d, 1H), 8.55 (d,1H), 8.50 (s, 1H), 8.02 (d, 2H), 7.53 (m, 5H), 6.91 (d, 1H), 4.84 (t,2H), 4.66 (t, 2H): MS (+ve ESI): 453 (M+H)⁺.

EXAMPLE 4

Preparation of Compound 4 in Table 1

An analogous reaction to that described in example 1, but starting with4-chloro-7-(3-morpholinopropoxy)quinoline (0.107 g, 0.35 mmol) andheating the reaction at 80° C. for 2 hours, yielded the title compound(78 mg, 46%) as a white solid after flash chromatography on silica gel,eluting with 5-15% methanol in 1:1 ethyl acetate/dichloromethane:

¹H-NMR (DMSOd₆, trifluoroacetic acid): 8.92 (s, 2H), 8.68 (d, 1H), 8.55(d, 1H), 8.01 (d, 2H), 7.57 (m, 5H), 6.90 (d, 1H), 4.32 (t, 2H), 4.01(d, 2H), 3.79 (t, 2H), 3.53 (d, 2H), 3.38 (m, 2H), 3.15 (m, 2H), 2.33(m, 2H) MS (+ve ESI): 485 (M+H)⁺.

EXAMPLE 5

Preparation of Compound 5 in Table 1

An analogous reaction to that described in example 1, but starting with4-chloro-7-(2-methoxyethoxy)quinoline (0.107 g, 0.45 mmol) and heatingfor 3 hours, yielded the title compound (35 mg, 19%) as a white solidafter flash chromatography on silica gel, eluting with 5-10% methanol in1:1 ethyl acetate/dichloromethane:

¹H-NMR (DMSOd₆, trifluoroacetic acid): 8.83 (s, 2H), 8.51 (d, 1H), 8.45(d, 1H), 7.93 (d, 2H), 7.54 (t, 1H), 7.45 (m, 3H), 7.31 (d, 1H), 6.80(d, 1H), 4.26 (m, 2H), 3.69 (m, 2H), 3.26 (s, 3H): MS (+ve ESI): 416(M+H)⁺.

EXAMPLE 6

Preparation of Compound 6 in Table 1

An analogous reaction to that described in example 1, but starting with4-chloro-7-(2-(2-methoxyethoxy)ethoxy)quinoline (0.112 g, 0.4 mmol) andheating for 3 hours, yielded the title compound (30 mg, 16%) as a whitesolid after flash chromatography on silica gel, eluting with 5-10%methanol in 1:1 ethyl acetate/dichloromethane:

¹H-NMR (DMSOd₆, trifluoroacetic acid): 8.90 (s, 2H), 8.59 (d, 1H), 8.52(d, 1H), 8.00 (d, 2H), 7.60 (t, 1H), 7.54 (m, 3H), 7.39 (s, 1H), 6.88(d, 1H), 4.33 (t, 2H), 3.85 (t, 2H), 3.63 (m, 2H), 3.48 (m, 2H), 3.25(s, 3H): MS (+ve ESI): 460 (M+H)⁺.

EXAMPLE 7

Preparation of Compound 7 in Table 1

2-(N-Benzoyl) 2,5-diaminopyrimidine (32 mg, 0.15 mmol) was added to asolution of N-acetyl-4-chloro-6-aminoquinoline (33 mg, 0.15 mmol) inisopropanol (2.0 ml) and the reaction heated at 82° C. for 3 hoursbefore the reaction was allowed to cool to ambient temperature.Hydrochloric acid (0.15 ml of a 1.0 N solution in diethyl ether, 0.15mmol) was added and the reaction heated at 82° C. for a further 3 hoursbefore being allowed to cool to ambient temperature. Diethyl ether (7.5ml) was added and the solid which precipitated was collected by suction.Purification by preparative reverse-phase hplc yielded the titlecompound (9.9 mg, 15% yield) as a white solid:

MS (+ve ESI): 399 (M+H)⁺.

EXAMPLE 8

Preparation of Compound 8 in Table 1

An analogous reaction to that described in example 7, but starting with4,5-dichloroquinoline (30 mg, 0.15 mmol), yielded the title compound(37.8 mg, 61% yield) as a white solid:

¹H-NMR (DMSO d₆): 11.24 (s, 1H), 8.54 (d, 1H, J=8 Hz), 8.08 (d, 1H, J=8Hz), 7.87-7.99 (m, 4H), 7.50-7.64 (m, 3H), 6.94 (d, 1H, J=8 Hz): MS (+veESI): 376 (M+H)⁺

EXAMPLE 9

Preparation of Compound 9 in Table 1

An analogous reaction to that described in example 7, but starting with4-chloro-5-cyanoquinoline (29 mg, 0.15 mmol), yielded the title compound(26.7 mg, 44% yield) as a white solid:

¹H-NMR (DMSO d₆): 11.24 (s, 1H), 9.34 (s, 1H), 8.90 (s, 2H), 8.68 (d,1H, J=8 HZ), 8.34 (d, 1H, J=8 Hz), 8.17 (d, 1H, J=8 Hz), 7.99 (d, 2H,J=8 Hz), 7.46-7.65 (m, 3H), 7.08 (d, 1H, J=8 Hz): MS (+ve ESI): 367(M+H)⁺ MS (−ve ESI): 365 (M−H)⁻

EXAMPLE 10

Preparation of Compound 10 in Table 1

An analogous reaction to that described in example 7, but starting with4-chloro-5,7-dimethylquinoline (29 mg, 0.15 mmol), yielded the titlecompound (5.6 mg, 9% yield) as a white solid:

¹H-NMR (DMSO d₆): 10.44 (bs, 1H), 8.48 (s, 2H), 8.00-8.04 (m, 3H),7.33-7.62 (m, 6H), 7.06 (s, 1H), 2.93 (s, 3H), 2.44 (s, 3H): MS (+veESI): 370 (M+H)⁺ MS (−ve ESI): 368 (M−H)⁻.

EXAMPLE 11

Preparation of Compound 11 in Table 1

An analogous reaction to that described in example 7, but starting with4,7-dichloroquinoline (30 mg, 0.15 mmol), yielded the title compound(28.3 mg, 46% yield) as a white solid:

¹H-NMR (DMSO d₆): 11.24 (s, 1H), 11.13 (s, 1H), 8.91 (s, 2H), 8.80 (d,1H, J=8 Hz), 8.62 (d, 1H, J=8 Hz), 8.15 (s, 1H), 7.94-7.99 (m, 3H),7.50-7.65 (m, 3H), 6.99 (d, 1H, J=8 Hz): MS (+ve ESI): 376 (M+H)⁺.

EXAMPLE 12

Preparation of Compound 12 in Table 1

An analogous reaction to that described in example 7, but starting with4-chloroquinoline (24 mg, 0.15 mmol), yielded the title compound (9.9mg, 17% yield) as a white solid

¹H-NMR (DMSO d₆): 11.02 (s, 1H), 8.79 (s, 2H), 8.48 (d, 1H, J=6 Hz),8.39 (d, 1H, J=8 Hz), 7.98 (d, 2H, J=8 Hz), 7.91 (d, 1H, J=8 Hz),7.72-7.78 (m, 1H), 7.48-7.63 (m, 4H), 6.87 (d, 1H, J=6 Hz): MS (+veESI): 342 (M+H)⁺.

EXAMPLE 13

Preparation of Compound 13 in Table 1

An analogous reaction to that described in example 7, but starting with4-chloro-7-(trifluoromethyl)quinoline (35 mg, 0.15 mmol), yielded thetitle compound (27.9 mg, 42% yield) as a white solid:

¹H-NMR (DMSO d₆): 11.25 (s, 1H), 9.00 (d, 1H, J=8 Hz), 8.92 (s, 2H),8.74 (d, 1H, J=8 Hz), 8.45 (s, 1H), 8.20 (d, 1H, J=8 Hz), 7.99 (d, 2H,J=8 Hz), 7.50-7.64 (m, 4H), 7.10 (d, 1H, J=8 Hz): MS (+ve ESI): 410(M+H)⁺ MS (−ve ESI): 408 (M−H)⁻.

EXAMPLE 14

Preparation of Compound 14 in Table 1

An analogous reaction to that described in example 7, but starting with4-chloro-6-(trifluoromethyl)quinoline (35 mg, 0.15 mmol), yielded thetitle compound (7.5 mg, 11% yield) as a white solid:

MS (+ve ESI): 410 (M+H)⁻.

Biological Data

The compounds of the invention inhibit the serine/threonine kinaseactivity of the aurora2 kinase and thus inhibit the cell cycle and cellproliferation. These properties may be assessed, for example, using oneor more of the procedures set out below:

(a) In Vitro Aurora2 Kinase Inhibition Test

This assay determines the ability of a test compound to inhibitserine/threonine kinase activity. DNA encoding aurora2 may be obtainedby total gene synthesis or by cloning. This DNA may then be expressed ina suitable expression system to obtain polypeptide with serine/threoninekinase activity. In the case of aurora2, the coding sequence wasisolated from cDNA by polymerase chain reaction (PCR) and cloned intothe BamH1 and Not1 restriction endonuclease sites of the baculovirusexpression vector pFastBac HTc (GibcoBRL/Life technologies). The 5′ PCRprimer contained a recognition sequence for the restriction endonucleaseBamH1 5′ to the aurora2 coding sequence. This allowed the insertion ofthe aurora2 gene in frame with the 6 histidine residues, spacer regionand rTEV protease cleavage site encoded by the pFastBac HTc vector. The3′ PCR primer replaced the aurora2 stop codon with additional codingsequence followed by a stop codon and a recognition sequence for therestriction endonuclease Not1. This additional coding sequence (5′ TACCCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3′) encoded for the polypeptidesequence YPYDVPDYAS. This sequence, derived from the influenzahemagglutin protein, is frequently used as a tag epitope sequence thatcan be identified using specific monoclonal antibodies. The recombinantpFastBac vector therefore encoded for an N-terminally 6 his tagged, Cterminally influenza hemagglutin epitope tagged aurora2 protein. Detailsof the methods for the assembly of recombinant DNA molecules can befound in standard texts, for example Sambrook et al. 1989, MolecularCloning—A Laboratory Manual, 2^(nd) Edition, Cold Spring HarborLaboratory press and Ausubel et al. 1999, Current Protocols in MolecularBiology, John Wiley and Sons Inc.

Production of recombinant virus can be performed followingmanufacturer's protocol from GibcoBRL. Briefly, the pFastBac-1 vectorcarrying the aurora2 gene was transformed into E. coli DH10Bac cellscontaining the baculovirus genome (bacmid DNA) and via a transpositionevent in the cells, a region of the pFastBac vector containinggentamycin resistance gene and the aurora2 gene including thebaculovirus polyhedrin promoter was transposed directly into the bacmidDNA. By selection on gentamycin, kanamycin, tetracycline and X-gal,resultant white colonies should contain recombinant bacmid DNA encodingaurora2. Bacmid DNA was extracted from a small scale culture of severalBH10Bac white colonies and transfected into Spodoptera frugiperda Sf21cells grown in TC100 medium (GibcoBRL) containing 10% serum usingCellFECTIN reagent (GibcoBRL) following manufacturer's instructions.Virus particles were harvested by collecting cell culture medium 72 hrspost transfection. 0.5 mls of medium was used to infect 100 mlsuspension culture of Sf21s containing 1×10⁷ cells/ml. Cell culturemedium was harvested 48 hrs post infection and virus titre determinedusing a standard plaque assay procedure. Virus stocks were used toinfect Sf9 and “High 5” cells at a multiplicity of infection (MOI) of 3to ascertain expression of recombinant aurora2 protein.

For the large scale expression of aurora2 kinase activity, Sf21 insectcells were grown at 28° C. in TC100 medium supplemented with 10% foetalcalf serum (Viralex) and 0.2% F68 Pluronic (Sigma) on a Wheaton rollerrig at 3 r.p.m. When the cell density reached 1.2×10⁶ cells ml⁻¹ theywere infected with plaque-pure aurora2 recombinant virus at amultiplicity of infection of 1 and harvested 48 hours later. Allsubsequent purification steps were performed at 4° C. Frozen insect cellpellets containing a total of 2.0×10 ⁸ cells were thawed and dilutedwith lysis buffer (25 mM HEPES(N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulphonic acid]) pH7.4 at 4°C., 100 mM KCl, 25 mM NaF, 1 mM Na₃VO₄, 1 mM PMSF (phenylmethylsulphonylfluoride), 2 mM 2-mercaptoethanol, 2 mM imidazole, 1 μg/ml aprotinin, 1μg/ml pepstatin, 1 μg/ml leupeptin), using 1.0 ml per 3×10⁷ cells. Lysiswas achieved using a dounce homogeniser, following which the lysate wascentrifuged at 41,000 g for 35 minutes. Aspirated supernatant was pumpedonto a 5 mm diameter chromatography column containing 500 μl Ni NTA(nitrilo-tri-acetic acid) agarose (Qiagen, product no. 30250) which hadbeen equilibrated in lysis buffer. A baseline level of UV absorbance forthe eluent was reached after washing the column with 12 ml of lysisbuffer followed by 7 ml of wash buffer (25 mM HEPES pH7.4 at 4° C., 100mM KCl, 20 mM imidazole, 2 mM 2-mercaptoethanol). Bound aurora2 proteinwas eluted from the column using elution buffer (25 mM HEPES pH7.4 at 4°C., 100 mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). An elutionfraction (2.5 ml) corresponding to the peak in UV absorbance wascollected. The elution fraction, containing active aurora2 kinase, wasdialysed exhaustively against dialysis buffer (25 mM HEPES pH7.4 at 4°C., 45% glycerol (v/v), 100 mM KCl, 0.25% Nonidet P40 (v/v), 1 mMdithiothreitol).

Each new batch of aurora2 enzyme was titrated in the assay by dilutionwith enzyme diluent (25mM Tris-HCl pH7.5, 12.5 mM KCl, 0.6 mM DTT). Fora typical batch, stock enzyme is diluted 1 in 666 with enzyme diluent &20 μl of dilute enzyme is used for each assay well. Test compounds (at10 mM in dimethylsulphoxide (DMSO)) were diluted with water & 10 μl ofdiluted compound was transferred to wells in the assay plates. “Total” &“blank” control wells contained 2.5% DMSO instead of compound. Twentymicrolitres of freshly diluted enzyme was added to all wells, apart from“blank” wells. Twenty microlitres of enzyme diluent was added to “blank”wells. Twenty microlitres of reaction mix (25 mM Tris-HCl, 78.4mM KCl,2.5mM NaF, 0.6 mM dithiothreitol, 6.25 mM MnCl₂, 6.25 mM ATP, 7.5 μMpeptide substrate [biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) containing 0.2μCi [γ³³P]ATP (Amersham Pharmacia, specific activity ≧2500 Ci/mmol) wasthen added to all test wells to start the reaction. The plates wereincubated at room temperature for 60 minutes. To stop the reaction 100μl 20% v/v orthophosphoric acid was added to all wells. The peptidesubstrate was captured on positively-charged nitrocellulose P30filtermat (Whatman) using a 96-well plate harvester (TomTek) & thenassayed for incorporation of ³³P with a Beta plate counter. “Blank” (noenzyme) and “total” (no compound) control values were used to determinethe dilution range of test compound which gave 50% inhibition of enzymeactivity.

For example, in this test, compounds 1, 2 and 4 in Table 1 gave 50%inhibition of enzyme activity at a concentration of 0.0521 μM, 0.059211μM and 0.0785 μM respectively.

(b) In Vitro Cell Proliferation Assays

These and other assays can be used to determine the ability of a testcompound to inhibit the growth of adherent mammalian cell lines, forexample the human tumour cell line MCF7.

Assay 1

MCF-7 (ATCC HTB-22) or other adherent cells were typically seeded at1×10³ cells per well (excluding the peripheral wells) in DMEM (SigmaAldrich) without phenol red, plus 10% foetal calf serum, 1% L-glutamineand 1% penicillin/streptomycin in 96 well tissue culture treated clearplates (Costar). The following day (day 1), the media was removed from ano treatment control plate and the plate stored at −80° C. The remainingplates were dosed with compound (diluted from 10 mM stock in DMSO usingDMEM (without phenol red, 10% FCS, 1% L-glutamine, 1%penicillin/streptomycin). Untreated control wells were included on eachplate. After 3 days in the presence/absence of compound (day 4) themedia was removed and the plates stored at −80° C. Twenty four hourslater the plates were thawed at room temperature and cell densitydetermined using the CyQUANT cell proliferation assay kit (c-7026/c-7027Molecular Probes Inc.) according to manufacturers directions. Briefly,200 ml of a cell lysis/dye mixture (10 ml of 20× cell lysis buffer B,190 ml of sterile water, 0.25 ml of CYQUANT GR dye) was added to eachwell and the plates incubated at room temperature for 5 minutes in thedark. The fluorescence of the wells was then measured using afluorescence microplate reader (gain 70, 2 reads per well, 1 cycle withexcitation 485 nm and emission 530 nm using a CytoFluor plate reader(PerSeptive Biosystems Inc.)). The values from day 1 and day 4 (compoundtreated) together with the values from the untreated cells were used todetermine the dilution range of a test compound that gave 50% inhibitionof cell proliferation. Compounds 1, 2 and 4 in Table 1 were effective inthis test at concentrations of 0.36 mM, 0.456 mM and 0.185 mMrespectively. These values could also be used to calculate the dilutionrange of a test compound at which the cell density dropped below the day1 control value. This indicates the cytotoxicity of the compound.Assay II

This assay determines the ability of at test compound to inhibit theincorporation of the thymidine analogue, 5′-bromo-2′-deoxy-uridine(BrdU) into cellular DNA. MCF-7 or other adherent cells were typicallyseeded at 0.8×10⁴ cells per well in DMEM (Sigma Aldrich) without phenolred, plus 10% foetal calf serum, 1% L-glutamine and 1%penicillin/streptomycin (50 μl/well) in 96 well tissue culture treated96 well plates (Costar) and allowed to adhere overnight. The followingday the cells were dosed with compound (diluted from 10 mM stock in DMSOusing DMEM (without phenol red, 10% FCS, 1% L-glutamine, 1%penicillin/streptomycin). Untreated control wells and wells containing acompound known to give 100% inhibition of BrdU incorporation wereincluded on each plate. After 48 hours in the presence/absence of testcompound the ability of the cells to incorporate BrdU over a 2 hourlabelling period was determined using a Boehringer (Roche) CellProliferation BrdU ELISA kit (cat. No. 1 647 229) according tomanufacturers directions. Briefly, 15 μl of BrdU labelling reagent(diluted 1:100 in media—DMEM no phenol red, 10% FCS, 1% L-glutamine, 1%penicillin/streptomycin) was added to each well and the plate returnedto a humidified (+5% CO₂) 37° C. incubator for 2 hours. After 2 hoursthe labelling reagent was removed by decanting and tapping the plate ona paper towel. FixDenat solution (50 μl per well) was added and theplates incubated at room temperature for 45 mins with shaking. TheFixDenat solution was removed by decanting and tapping the invertedplate on a paper towel. The plate was then washed once with phosphatebuffered saline (PBS) and 100 μl/well of Anti-BrdU-POD antibody solution(diluted 1:100 in antibody dilution buffer) added. The plate was thenincubated at room temperature with shaking for 90 min. UnboundAnti-BrdU-POD antibody was removed by decanting and washing the plate 5times with PBS before being blotted dry. TMB substrate solution wasadded (100 μl/well) and incubated for approximately 10 minutes at roomtemperature with shaking until a colour change was apparent. The opticaldensity of the wells was then determined at 690 nm wavelength using aTitertek Multiscan plate reader. The values from compound treated,untreated and 100% inhibition controls were used to determine thedilution range of a test compound that gave 50% inhibition of BrdUincorporation. For instance, compounds 1, 2 and 4 in Table 1 wereeffective in this test at 0.36 μM, 0.46 μM and 0.19 μM respectively.

(c) In Vitro Cell Cycle Analysis Assay

This assay determines the ability of a test compound to arrest cells inspecific phases of the cell cycle. Many different mammalian cell linescould be used in this assay and MCF7 cells are included here as anexample. MCF-7 cells were seeded at 3×10⁵ cells per T25 flask (Costar)in 5 ml DMEM (no phenol red 10% FCS, 1% L-glutamine 1%penicillin/streptomycin). Flasks were then incubated overnight in ahumidified 37° C. incubator with 5% CO₂. The following day 1 ml of DMEM(no phenol red 10% FCS, 1% L-glutamine 1% penicillin/streptomycin)carrying the appropriate concentration of test compound solubilised inDMSO was added to the flask. A no compound control treatments was alsoincluded (0.5% DMSO). The cells were then incubated for a defined time(usually 24 hours) with compound. After this time the media wasaspirated from the cells and they were washed with 5 ml of prewarmed(37° C.) sterile PBSA, then detached from the flask by brief incubationwith trypsin and followed by resuspension in 10 ml of 1% Bovine SerumAlbumin (BSA, Sigma-Aldrich Co.) in sterile PBSA. The samples were thencentrifuged at 2200 rpm for 10 min. The supernatant was aspirated andthe cell pellet was resuspended in 200 μl of 0.1% (w/v) Tris sodiumcitrate, 0.0564% (w/v) NaCl, 0.03% (v/v) Nonidet NP40, [pH 7.6].Propridium Iodide (Sigma Aldrich Co.) was added to 40 μg/ml and RNAase A(Sigma Aldrich Co.) to 100 μg/ml. The cells were then incubated at 37 °C. for 30 minutes. The samples were centrifuged at 2200 rpm for 10 min,the supernatant removed and the remaining pellet (nuclei) resuspended in200 μl of sterile PBSA. Each sample was then syringed 10 times using 21gauge needle. The samples were then transferred to LPS tubes and DNAcontent per cell analysed by Fluorescence activated cell sorting (FACS)using a FACScan flow cytometer (Becton Dickinson). Typically 25000events were counted and recorded using CellQuest v1.1 software (VeritySoftware). Cell cycle distribution of the population was calculatedusing Modfit software (Verity Software) and expressed as percentage ofcells in G0/G1, S and G2/M phases of the cell cycle.

Compounds of the invention showed activity in this assay.

1. A compound of formula (I)

or a salt, in vivo hydrolysable ester or amide thereof; where R⁵ is agroup of sub-formula (iii), (iv) or (v)

where R⁸⁰ is a substituent and R⁸¹is hydrogen or a substituent; where asubstituent is independently selected from halo, C₁₋₄alkyl, optionallysubstituted C₁₋₆alkoxy (where suitable optional substituents are halo,perhaloalkyl, mercapto, thioalkyl, hydroxy, carboxy, alkoxy, heteroaryl,heteroaryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, alkenyloxy,alkynyloxy, alkoxyalkoxy, aryloxy (where the aryl group may besubstituted by halo, nitro, or hydroxy), cyano, nitro, amino, mono- ordi-alkyl amino, oximino or S(O)_(y)R⁹⁰ where y is 0 or an integer of 1-3and R⁹⁰ is alkyl), C₁₋₄alkoxymethyl, di(C₁₋₄alkoxy)methyl, C₁₋₄alkanoyl,trifluoromethyl, cyano, amino, C₂₋₅alkenyl, C₂₋₅alkynyl, a phenyl group,a benzyl group or a 5-6-membered heterocyclic group with 1-3heteroatoms, selected independently from 0, S and N, which heterocyclicgroup may be aromatic or non-aromatic and may be saturated (linked via aring carbon or nitrogen atom) or unsaturated (linked via a ring carbonatom), and which phenyl, benzyl or heterocyclic group may bear on one ormore ring carbon atoms up to 5 substituents selected from hydroxy,halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy, trifluoromethyl,cyano, amino, nitro, C₂₋₄alkanoyl, C₁₋₄alkanoylamino,C₁₋₄alkoxycarbonyl, C₁₋₄alkylsulphanyl, C₁₋₄alkylsulphinyl,C₁₋₄alkylsulphonyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,N,N-di(C₁₋₄alkyl)aminosulphonyl, C₁₋₄alkylsulphonylamino, and asaturated heterocyclic group selected from morpholino, thiomorpholino,pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl,which saturated heterocyclic group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno, C₁₋₃alkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,trifluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl; or asubstituent is selected from carboxamido, carboxy and benzoyl; or asubstituent is a group of sub-formula (II)

where q′ is 0, 1, 2, 3 or 4; s′ is 0or 1; X¹² is C(O) or S(O₂); R⁷⁰ ishydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino, N—C₁₋₆alkylamino,N,N-(C₁₋₆alkyl)₂amino, hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy,aminoC₂₋₆alkoxy, N—C₁₋₆alkylaminoC₂₋₆alkoxy,N,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy or C₃₋₇cycloalkyl, or R⁷⁰ is of theFormula (III):—K-J  (III) wherein J is aryl, heteroaryl or heterocyclyl and K is abond, oxy, imino, N—(C₁₋₆alkyl)imino, oxyC₁₋₆alkylene,iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)iminoC₁₋₆alkylene, —NHC(O)—, —SO₂NH—,—NHSO₂— or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl orheterocyclyl group in a R⁷⁰ group may be optionally substituted by oneor more groups selected from hydroxy, halo, trifluoromethyl, cyano,mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, —O—(C₁₋₃alkyl)—O—,C₁₋₆alkylS(O)_(n)— (wherein n is 0-2), N—C₁₋₆alkylamino,N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl, N—C₁₋₆alkylcarbamoyl,N,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, C₁₋₆alkanoyloxy,C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl, N,N-(C₁₋₆alkyl)₂sulphamoyl,C₁₋₆alkylsulphonylamino and C₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, andsuitably also oxo, or any aryl, heteroaryl or heterocyclyl group in aR⁷⁰ group may be optionally substituted with one or more groups of theFormula (IV):—B¹—(CH₂)_(p)-A¹  (IV) wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano,amino, N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl orN,N-(C₁₋₆alkyl)₂carbamoyl, p is 1-6, and B¹ is a bond, oxy, imino,N—(C₁₋₆alkyl)imino or —NHC(O)—, with the proviso that p is 2 or moreunless B¹ is a bond or —NHC(O)—; or any aryl, heteroaryl or heterocyclylgroup in a R⁷⁰ group may be optionally substituted with one or moregroups of the Formula (V):-E¹-D¹  (V) wherein D¹ is aryl, heteroaryl or heterocyclyl and E¹ is abond, C₁₋₆alkylene, oxyC₁₋₆alkylene, oxy, imino, N—(C₁₋₆alkyl)imino,iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene,C₁₋₆alkylene-oxyC₁₋₆alkylene, C₁₋₆alkylene-iminoC₁₋₆alkylene,C₁₋₆alkylene-N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH—or —NHC(O)—C₁₋₆alkylene-, and any aryl, heteroaryl or heterocyclyl groupin a substituent may be optionally substituted with one or more groupsselected from hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkoxy, carboxy,C₁₋₆alkoxycarbonyl, carbamoyl, N—C₁₋₆alkylcarbamoyl,N—(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl, amino, N—C₁₋₆alkylamino andN,N-(C₁₋₆alkyl)₂amino, and any C₃₋₇cycloalkyl or heterocyclyl group in aR⁷⁰ group may be optionally substituted with one or two oxo or thioxosubstituents, and any of the R⁷⁰ groups defined hereinbefore whichcomprises a CH₂ group which is attached to 2 carbon atoms or a CH₃ groupwhich is attached to a carbon atom may optionally bear on each said CH₂or CH₃ group a substituent selected from hydroxy, amino, C₁₋₆alkoxy,N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino and heterocyclyl; and R⁹⁹ ishydrogen or a group C(O)R⁷⁰ where R⁷⁰ is as defined above; or R⁷⁰ may becycloalkenyl or cycloalkynyl, alkenyl optionally substituted by aryl oralkyl substituted by cycloalkenyl; or a substituent is a group—X¹⁰(CH₂)_(p′)—X¹¹R¹⁰⁰ or —X¹³R¹⁰⁰ where p′ is 1-3, X¹⁰ and X¹¹ areindependently selected from a bond, —O—, —S— or NR¹⁰¹—where R¹⁰¹ ishydrogen or a C₁₋₃alkyl, provided that one of X¹⁰ or X¹¹ is a bond; X¹³is —O—, —S— or NR¹⁰²—where R¹⁰² is hydrogen or a C₁₋₄alkyl and R¹⁰⁰ isR⁷⁰; or a substituent is a group of formula (VI)

where R⁷¹ and R⁷² are independently selected from hydrogen or C₁₋₄alkyl,or R⁷¹ and R⁷² together form a bond, and R⁷³ is a group OR⁷⁴, NR⁷⁵R⁷⁶where R⁷⁴ is C₁₋₄alkyl and one of R⁷⁵ or R⁷⁶ is hydrogen and the otheris C₁₋₆alkyl optionally substituted with trifluoromethyl, C₁₋₃ alkoxy,cyano, thioC₁₋₄alkyl, or indane or furan optionally substituted withC₁₋₄ alkyl, or one of R⁷⁵ or R⁷⁶ is hydrogen and the other is pyridine,or a phenyl group optionally substituted with one or more groupsselected from halo, nitro, alkyl or alkoxy; and R⁷⁵ and R⁷⁶ mayadditionally form together with the nitrogen atom to which they areattached, an aromatic or non-aromatic heterocyclic ring which maycontain further heteroatoms; or a substituent is a group of sub-formula(VII)

where p″ is 0 or 1 and R⁸³ and R⁸⁴ are C₁₋₄alkyl substituted bycycloalkyl; C₁₋₆alkylthio; C₁₋₆alkylthio; or a group —(CH₂)_(q)R⁷⁰ whereq and R⁷⁰ are as defined above in relation to formula (II) or one of R⁸³or R⁸⁴ is hydrogen, or methyl, ethyl or propyl optionally substitutedwith hydroxy or R⁸³ or R⁸⁴ is optionally substituted aryl group selectedfrom phenyl optionally substituted with one or more groups selected fromC₁₋₆alkyl or halo, hydroxy, alkoxy, trifluoromethyl, nitro, cyano,trifluromethoxy, CONH₂, C(O)CH₃, amino, or dimethylamine or R⁸³ or R⁸⁴is an optionally substituted alkyl group selected from C₁₋₆alkyl group,optionally substituted with one or more cyano, hydroxy, alkoxy,alkylthio, COOalkyl, or aryl optionally substituted with C₁₋₆ alkyl orhalo, hydroxy, alkoxy, trifluoromethyl, nitro, cyano, trifluromethoxy,CONH₂, C(O)CH₃, amino, or dimethylamine, or N-methyl pyrrole; or R⁸³ andR⁸⁴ is cyclohexyl optionally substituted with hydroxy; or R⁸³ and R⁸⁴ isprop-2-enyl; or R⁸³ or R⁸⁴ is optionally substituted heterocyclyl, orR⁸³ and R⁸⁴ together form a heterocyclic group, which may both beselected from piperadine, piperazine, morpholino, pyrrolidine orpyridine any of which may be optionally substituted with hydroxy,alkoxy, or alkyl which may itself be substituted with a hydroxy group;and R¹, R², R³, R⁴ are independently selected from halogeno, cyano,nitro, C₁₋₃alkylsulphanyl, —N(OH)R⁷— (wherein R⁷ is hydrogen, orC₁₋₃alkyl), or R⁹X¹—wherein at least one group R¹, R², R³, R⁴ is a groupR⁹X¹—(wherein X¹ represents a direct bond, —O—, —CH₂—, —OC(O)—, —C(O)—,—S—, —SO—, —SO₂—, —NR¹⁰C(O)—, —C(O)NR¹¹—, —SO₂NR¹²—, —NR¹³SO₂— or—NR¹⁴—(wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ each independently representshydrogen, hydroxyC₁₋₄alkyl C₁₋₃alkoxy or C₁₋₃alkoxyC₂₋₃alkyl)), and R⁹is selected from one of the following twenty-two groups: 1) hydrogen orC₁₋₅alkyl which may be unsubstituted or which may be substituted withone or more groups selected from hydroxy, oxiranyl, fluoro, chloro,bromo, amino, C₁₋₃alkyl and trifluoromethyl); 2) —R^(a)X²C(O)R¹⁵(wherein X² represents —O— or —NR¹⁶— (in which R¹⁶ represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁵ represents C₁₋₃alkyl, —NR¹⁷R¹⁸or —OR¹⁹ (wherein R¹⁷, R¹⁸ and R¹⁹ which may be the same or differenteach represents hydrogen, C₁₋₅alkyl, hydroxyC₁₋₅alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3) —R^(b)X³R²⁰ (wherein X³ represents —O—,C(O)—S—, —SO—, —SO₂—, —OC(O)—, —NR²¹C(O)_(s)—, —C(O)NR²²—, —SO₂NR²³—,—NR²⁴SO₂— or —NR²⁵—(wherein R²¹, R²², R²³, R²⁴ and R²⁵ eachindependently represents hydrogen, C₁₋₃alkyl, hydroxy C₁₋₄alkyl orC₁₋₃alkoxyC₂₋₃alkyl and s is 1 or 2) and R²⁰ represents hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl or a 5-6-membered saturated heterocyclic group with1-2 heteroatoms, selected independently from O, S and N, which C₁₋₆alkylgroup may bear 1, 2 or 3 substituents selected from oxo, hydroxy,halogeno, cyclopropyl, amino, C₁₋₄alkylamino,C₁₋₄alkanoyldi-C₁₋₄alkylamino, C₁₋₄alkylthio, C₁₋₄alkoxy and whichcyclic group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(R^(b′))_(g)D (wherein f is 0 or 1, g is 0 or 1 and D is acyclic group selected from C₃₋₆cycloalkyl group, an aryl group or a5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selectedindependently from O, S and N, which cyclic group may bear one or moresubstituents selected from halo or C₁₋₄alkyl)); 4) —R^(c)X⁴R^(c′)X⁵R²⁶(wherein X⁴ and X⁵ which may be the same or different are each —O—,C(O), —S—, —SO—, —SO₂—, —NR²⁷C(O)_(s)—, —C(O)_(x)NR²⁸—, —SO₂NR²⁹—,—NR³⁰SO₂— or —NR³¹—(wherein R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl ands is 1 or 2) and R²⁶ represents hydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl); 5) R³² wherein R³² is a C₃₋₆ cycloalkyl orsaturated heterocyclic ring (linked via carbon or nitrogen), with 1-2heteroatoms, selected independently from O, S and N, which cycloalkyl orheterocyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, cyanoC₁₋₄alkyl,cyclopropyl, C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl,carboxamido, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, C₁₋₄alkanoyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy, nitro, amino,C₁₋₄alkoxy, C₁₋₄hydroxyalkoxy, carboxy, trifluoromethyl, —C(O)NR³⁸R³⁹,—NR⁴⁰C(O)R⁴¹ (wherein R³⁸, R³⁹, R⁴⁰ and R⁴¹, which may be the same ordifferent, each represents hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and a group —(—O—)_(f)(R^(b′))_(g)D (wherein f is 0or 1, g is 0 or 1 and D is a cyclic group selected from C₃₋₆cycloalkyl,aryl group or a 5-6-membered saturated or unsaturated heterocyclic groupwith 1-2 heteroatoms, selected independently from O, S and N, whichcyclic group may bear one or more substituents selected from halo andC₁₋₄alkyl); 6) —R^(d)R³² (wherein R³² is as defined hereinbefore); 7)—R^(e)R³² (wherein R³² is as defined hereinbefore); 8) —R^(f)R³²(wherein R³² is as defined hereinbefore); 9) R³³ (wherein R³³ representsa pyridone group a phenyl group or a 5-6-membered aromatic heterocyclicgroup (linked via carbon or nitrogen) with 1-3 heteroatoms selected fromO, N and S, which pyridone, phenyl or aromatic heterocyclic group maycarry up to 5 substituents selected from hydroxy, nitro, halogeno,amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, oxo, cyanoC₁₋₄alkyl, cyclopropyl,C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, C₁₋₄alkanoyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy, carboxy,carboxamido, trifluoromethyl, cyano, —C(O)NR³⁸R³⁹, —NR⁴⁰C(O)R⁴¹ (whereinR³⁸, R³⁹, R⁴⁰ and R⁴¹, which may be the same or different, eachrepresents hydrogen, C₁₋₄alkyl, hydroxyC₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and a group —(—O—)_(f)(C₁₋₄alkyl)_(g)D (wherein f is 0 or 1, g is 0 or 1and D is a cyclic group selected from C₃₋₆cycloalkyl, aryl or5-6-membered saturated or unsaturated heterocyclic group with 1-2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from halo and C₁₋₄alkyl); 10)—R^(g)R³³ (wherein R³³ is as defined hereinbefore); 11) —R^(h)R³³(wherein R³³ is as defined hereinbefore); 12) —R^(i)R³³ (wherein R³³ isas defined hereinbefore); 13) —R^(j)X⁶R³³ (wherein X⁶ represents —O—,—C(O)—, —S—, —SO—, —SO₂—, —OC(O)—, —NR³⁸C(O)—, —C(O)NR³⁹—, —SO₂NR⁴⁰—,—NR⁴¹SO₂— or —NR⁴²—(wherein R³⁸, R³⁹, R⁴⁰, R⁴¹ and R⁴² eachindependently represents hydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 14)—R^(k)X⁷R³³ (wherein X⁷ represents —O—, C(O), —S—, —SO—, —SO₂—, —OC(O)—,—NR⁴³C(O)—, —C(O)NR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷—(wherein R⁴³, R⁴⁴,R⁴⁵, R⁴⁶ and R⁴⁷ each independently represents hydrogen, C₁₋₃alkyl,hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as definedhereinbefore); 15) —R^(m)X⁸R³³ (wherein X⁸ represents —O—, —C(O)—, —S—,—SO—, —SO₂—, —NR⁴⁸C(O)—, —C(O)NR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or—NR⁵²—(wherein R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹ and R⁵² each independently representshydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R³³ isas defined hereinbefore); 16) —R^(n)X⁹R^(n′)R³³ (wherein X⁹ represents—O—, —C(O)—, —S—, —SO—, —SO₂—, —NR⁵³C(O)—, —C(O)NR⁵⁴—, —SO₂NR⁵⁵—,NR⁵⁶SO₂— or —NR⁵⁷—(wherein R⁵³, R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ each independentlyrepresents hydrogen, C₁₋₃alkyl, hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)and R³³ is as defined hereinbefore); 17) —R^(p)X⁹—R^(p′)R³² (wherein X⁹and R³² are as defined hereinbefore); 18) C₂₋₅alkenyl which may beunsubstituted or which may be substituted with one or more groupsselected from hydroxy, fluoro, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino,aminosulphonyl, N—C₁₋₄alkylaminosulphonyl, andN,N-di(C₁₋₄alkyl)aminosulphonyl; 19) C₂₋₅alkynyl which may beunsubstituted or which may be substituted with one or more groupsselected from hydroxy, fluoro, C₁₋₄alkylamino, N,N-di(C₁₋₄alkyl)amino,aminosulphonyl, N—C₁₋₄alkylaminosulphonyl, andN,N-di(C₁₋₄alkyl)aminosulphonyl; 20) —R^(t)X⁹R^(t′)R³² (wherein X⁹ andR³² are as defined hereinbefore); 21) —R^(u)X⁹ R^(u′)R³² (wherein X⁹ andR³² are as defined hereinbefore); and 22)—R^(v)R⁵⁸(R^(v′))_(q)(X⁹)_(r)R⁵⁹(wherein X⁹ is as defined hereinbefore,q is 0 or 1, r is 0 or 1, and R⁵⁸ is a C₁₋₃alkylene group or a cyclicgroup selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclopentylene, cyclohexylene or a 5-6-membered saturated heterocyclicgroup with 1-2 heteroatoms, selected independently from O, S and N,which C₁₋₃alkylene group may bear 1, or 2 substituents selected fromoxo, hydroxy, halogeno, and C₁₋₄alkoxy and which cyclic group may bear 1or 2 substituents selected from oxo, hydroxy, halogeno, cyano,C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl, C₁₋₄alkoxycarbonyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ring D (wherein f is 0 or 1, g is 0 or 1 andring D is a cyclic group selected from C₃₋₆cycloalkyl, aryl or5-6-membered saturated or unsaturated heterocyclic group with 1-2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from halo or C₁₋₄alkyl); andR⁵⁹ is hydrogen, C₁₋₃alkyl, or a cyclic group selected from cycloalkyl,cyclobutyl, cyclopentyl, cyclopentylene, cyclohexylene or a 5-6-memberedsaturated heterocyclic group with 1-2 heteroatoms, selectedindependently from O, S and N, which C₁₋₃alkyl group may bear 1, or 2substituents selected from oxo, hydroxy, halogeno, and C₁₋₄alkoxy andwhich cyclic group may bear 1or 2 substituents selected from oxo,hydroxy, halogeno, cyano, C₁₋₄cyanoalkyl, C₁₋₄alkyl, C₁₋₄hydroxyalkyl,C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkylsulphonylC₁₋₄alkyl,C₁₋₄alkoxycarbonyl, C₁₋₄aminoalkyl, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino,C₁₋₄alkylaminoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,C₁₋₄alkylaminoC₁₋₄alkoxy, di(C₁₋₄alkyl)aminoC₁₋₄alkoxy and a group—(—O—)_(f)(C₁₋₄alkyl)_(g)ringD (wherein f is 0 or 1, g is 0 or 1 andring D is a cyclic group selected from C₃₋₆cycloalkyl, aryl or5-6-membered saturated or unsaturated heterocyclic group with 1-2heteroatoms, selected independently from O, S and N, which cyclic groupmay bear one or more substituents selected from halo or C₁₋₄alkyl); andwherein R^(a), R^(b), R^(b′), R^(c), R^(c′), R^(d), R^(g), R^(j), R^(n),R^(n′), R^(p), R^(p′), R^(t′), R^(u′), R^(v) and R^(v′) areindependently selected from C₁₋₈alkylene groups optionally substitutedby one or more substituents selected from hydroxy, halogeno, amino,R^(e)R^(h), R^(k) and R^(t) are independently selected fromC₂₋₈alkenylene groups optionally substituted by one or more substituentsselected from hydroxy, halogeno, amino, and R^(t) may additionally be abond; and R^(f), R^(i), R^(m) and R^(u) are independently selected fromby C₂₋₈alkynylene groups optionally substituted by one or moresubstituents selected from hydroxy, halogeno, amino; provided that atleast one of R² or R³ is other than hydrogen; and wherein unlessspecifically stated, the terms heterocyclyl, heterocyclic group andheterocyclic ring include aromatic or non-aromatic rings containing from4 to 20 ring atoms, at least one of which is a heteroatom selected fromoxygen, sulphur or nitrogen.
 2. A compound according to claim 1 where R¹is hydrogen and R⁴ is hydrogen, halo, C₁₋₄ alkyl or C₁₋₄alkoxy.
 3. Acompound according to claim 1 wherein at least one group R²or R³comprises a chain of at least 3 optionally substituted carbon atoms orheteroatoms selected from oxygen, nitrogen or sulphur, wherein saidchain is substituted by a polar group which assists solubility.
 4. Acompound of formula (VIII)

or a salt, in vivo hydrolysable ester or amide thereof; where Y is agroup —NR⁶C(O)—, —C(O)NR⁶—, —NR⁶S(O)₂—, —NHR⁶—, —NR⁶CH═N—,—C(═NR⁶)NR^(6′)—, —NR⁶C(═NR^(6′))NR^(6″)—, —C(O), —CH═CHC(O)NR⁶—,—C≡CC(O)NR⁶, —CH═CH—, —C≡C—, —S—, —S(O)—, —S(O)₂—, or —O—where R⁶,R^(6′) and R^(6″) are independently selected from hydrogen or C₁₋₄alkyl,q is 0 or an integer of from 1 to 6; R⁷⁰ is hydrogen, hydroxy,C₁₋₆alkyl, C₁₋₆alkoxy, amino, N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino,hydroxyC₂₋₆alkoxy, C₁₋₆alkoxyC₂₋₆alkoxy, aminoC₂₋₆alkoxyN—C₁₋₆alkylaminoC₂₋₆alkoxy, N,N-(C₁₋₆alkyl)₂aminoC₂₋₆alkoxy orC₃₋₇cycloalkyl optionally substituted with one or two oxo or thioxosubstituents, or R⁷⁰ is of the Formula (III):—K-J  (III) wherein J is an aryl or heterocyclyl group either of whichis optionally substituted with one or more groups selected from hydroxy,halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy,carbamoyl, formyl, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, —O—(C₁₋₃alkyl)—O—, C₁₋₆alkylS(O)_(n)—(wherein n is 0-2),N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, C₁₋₆alkoxycarbonyl,N—C₁₋₆alkylcarbamoyl, N,N-(C₁₋₆alkyl)₂carbamoyl, C₂₋₆alkanoyl,C₁₋₆alkanoyloxy, C₁₋₆alkanoylamino, N—C₁₋₆alkylsulphamoyl,N,N-(C₁₋₆alkyl)₂sulphamoyl, C₁₋₆alkylsulphonylamino andC₁₋₆alkylsulphonyl-N—(C₁₋₆alkyl)amino, or groups of the Formula (IV) or(V):—B¹—(CH₂)_(p)-A¹  (IV)-E¹-D¹  (V) wherein A¹ is halo, hydroxy, C₁₋₆alkoxy, cyano, amino,N—C₁₋₆alkylamino, N,N-(C₁₋₆alkyl)₂amino, carboxy, C₁₋₆alkoxycarbonyl,carbamoyl, N—C₁₋₆alkylcarbamoyl or N,N-(C₁₋₆alkyl)₂carbamoyl, p is 1-6;B¹ is a bond, oxy, imino, N—(C₁₋₆alkyl)imino or —NHC(O)—, with theproviso that p is 2 or more unless B¹ is a bond or —NHC(O)—; D¹ is arylor heterocyclyl; E¹ is a bond, C₁₋₆alkylene, oxyC₁₋₆alkylene, oxy,imino, N—(C₁₋₆alkyl)imino, iminoC₁₋₆alkylene,N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene, C₁₋₆alkylene-oxyC₁₋₆alkylene,C₁₋₆alkylene-iminoC₁₋₆alkylene,C₁₋₆alkylene-N—(C₁₋₆alkyl)-iminoC₁₋₆alkylene, —NHC(O)—, —NHSO₂—, —SO₂NH—or —NHC(O)—C₁₋₆alkylene-; or, in the case of heterocyclyl groups J,these may be optionally substituted with one or two oxo or thioxosubstituents; and K is a bond, oxy, imino, N—(C₁₋₆alkyl)imino,oxyC₁₋₆alkylene, iminoC₁₋₆alkylene, N—(C₁₋₆alkyl)iminoC₁₋₆alkylene,—NHC(O)—, —SO₂NH—, —NHSO₂— or —NHC(O)—C₁₋₆alkylene-, R^(x) is hydrogen,halo, C₁₋₄alkoxy, cyano, trifluoromethyl, or phenyl; and R¹, R², R³, R⁴are independently selected from halo, cyano, nitro, trifluoromethyl,C₁₋₃alkyl, —NR⁷R⁸ (wherein R⁷ and R⁸, which may be the same ordifferent, each represents hydrogen or C₁₋₃alkyl), or —X¹R⁹ (wherein X¹represents a direct bond, —O—, —CH₂—, —OCO—, carbonyl, —S—, —SO—, —SO₂—,—NR¹⁰CO—, —CONR¹¹—, —SO₂NR¹²—, —NR¹³SO₂— or —NR¹⁴— (wherein R¹⁰, R¹¹,R¹², R¹³ and R¹⁴ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl), and R⁹ is selected from one of the followingeighteen groups: 1) hydrogen or C₁₋₅alkyl which may be unsubstituted orwhich may be substituted with one or more groups selected from hydroxy,fluoro or amino; 2) C₁₋₅alkylX²COR¹⁵ (wherein X² represents —O— or—NR¹⁶—(in which R¹⁵ represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ represents C₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹(wherein R¹⁷, R¹⁸, and R¹⁹,which may be the same or different, eachrepresent hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 3)C₁₋₅alkylX³R²⁰ (wherein X³ represents —O—, —S—, —SO—, —SO₂—, —OCO—,—NR²¹CO—, —CONR²²—, —SO₂NR²³—, —NR²⁴SO₂— or —NR²⁵—(wherein R²¹, R²²,R²³, R²⁴ and R²⁵ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R²⁰ represents hydrogen, C₁₋₃alkyl,cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic groupwith 1-2 heteroatoms, selected independently from O, S and N, whichC₁₋₃alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy,halogeno and C₁₋₄alkoxy and which cyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4) C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²⁶ (whereinX⁴ and X⁵ which may be the same or different are each —O—, —S—, —SO—,—SO₂—, —NR²⁷CO—, —CONR²⁸—, —SO₂NR²⁹—, —NR³⁰SO₂— or —NR³¹— (whereinR²⁷R²⁸, R²⁹, R³⁰ and R³¹ each independently represents hydrogen,C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁶ represents hydrogen orC₁₋₃alkyl); 5) R³² (wherein R³² is a 5-6-membered saturated heterocyclicgroup (linked via carbon or nitrogen) with 1-2 heteroatoms, selectedindependently from O, S and N, which heterocyclic group may bear 1 or 2substituents selected from oxo, hydroxy, halogeno, C₁₋₄alkyl,C₁₋₄hydroxyalkyl, C₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl andC₁₋₄alkylsulphonylC₁₋₄alkyl); 6) C₁₋₅alkylR³² (wherein R³² is as definedhereinbefore); 7) C₂₋₅alkenylR³² (wherein R³² is as definedhereinbefore); 8) C₂₋₅alkynylR³² (wherein R³² is as definedhereinbefore); 9) R³³ (wherein R³³ represents a pyridone group, a phenylgroup or a 5-6-membered aromatic heterocyclic group (linked via carbonor nitrogen) with 1-3 heteroatoms selected from O, N and S, whichpyridone, phenyl or aromatic heterocyclic group may carry up to 5substituents on an available carbon atom selected from hydroxy,halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,trifluoromethyl, cyano, —CONR³⁴R³⁵ and —NR³⁶COR³⁷ (wherein R³⁴, R³⁵, R³⁶and R³⁷, which may be the same or different, each represents hydrogen,C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 10) C₁₋₅alkylR³³ (wherein R³³ is asdefined hereinbefore); 11) C₂₋₅alkenylR³³ (wherein R³³ is as definedhereinbefore); 12) C₂₋₅alkynylR³³ (wherein R³³ is as definedhereinbefore); 13) C₁₋₅alkylX⁶R³³ (wherein X⁶ represents —O—, —S—, —SO—,—SO₂—, —NR³⁸CO—, —CONR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸,R³⁹, R⁴⁰, R⁴¹ and R⁴² each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 14)C₂₋₅alkenylX⁷R³³ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—, —NR⁴³CO—,—CONR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷— (wherein R⁴³, R⁴⁴, R⁴⁵, R⁴⁶ andR⁴⁷ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 15)C₂₋₅alkynylX⁸R³³ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—, —NR⁴⁸CO—,—CONR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or —NR⁵²— (wherein R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹ andR⁵² each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 16)C₁₋₃alkylX⁹C₁₋₃alkylR³³ (wherein X⁹ represents —O—, —S—, —SO—, —SO₂—,—NR⁵³CO—, —CONR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or —NR⁵⁷— (wherein R⁵³, R⁵⁴,R⁵⁵, R⁵⁶ and R⁵⁷ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); and 17)C₁₋₃alkylX⁹C₁₋₃alkylR³² (wherein X⁹ and R²⁸ are as definedhereinbefore); and R¹ and R⁴ may additionally be hydrogen.
 5. A compoundaccording to claim 4 where Y is a group —NR⁶C(O)— or —C(O)NR⁶— where R⁶is defined in claim
 4. 6. A compound according to claim 1, wherein R⁸⁰is a group of sub-formula (II) and R⁸¹ is hydrogen or halo, C₁₋₄alkoxy,cyano, trifluoromethyl, or phenyl.
 7. A compound according to claim 1 orclaim 4, wherein R⁹ is selected from one of the following groups: 1′)hydrogen or C₁₋₅alkyl which may be unsubstituted or which may besubstituted with one or more groups selected from hydroxy, fluoro oramino, 2′) C₁₋₅alkylX²C(O)R¹⁵ (wherein X² represents —O— or —NR¹⁶— (inwhich R¹⁵ represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R⁵represents C₁₋₃alkyl, —NR¹⁷R¹⁸ or —OR¹⁹ (wherein R¹⁷, R¹⁸ and R¹⁹ whichmay be the same or different each represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl)); 3′) C₁₋₅alkylX³R²⁰ (wherein X³ represents —O—,—S—, —SO—, —SO₂—, —OCO—, —NR²¹CO—, —CONR²²—, —SO₂NR²³—, —NR²⁴SO₂— or—NR²⁵— (wherein R²¹, R²², R²³, R²⁴ and R²⁵ each independently representshydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R²⁰ represents hydrogen,C₁₋₃alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturatedheterocyclic group with 1-2 heteroatoms, selected independently from O,S and N, which C₁₋₃alkyl group may bear 1 or 2 substituents selectedfrom oxo, hydroxy, halogeno and C₁₋₄alkoxy and which cyclic group maybear 1 or 2 substituents selected from oxo, hydroxy, halogeno,C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy); 4′)C₁₋₅alkylX⁴C₁₋₅alkylX⁵R²⁶ (wherein X⁴ and X⁵ which may be the same ordifferent are each —O—, —S—, —SO—, —SO₂—, —NR²⁷CO—, —CONR²⁸—, —SO₂NR²⁹—,—NR³⁰SO₂— or —NR³¹— (wherein R²⁷, R²⁸, R²⁹, R³⁰ and R³¹ eachindependently represents hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) andR²⁶ represents hydrogen or C₁₋₃alkyl); 5′) R³² (wherein R³² is a5-6-membered saturated heterocyclic group (linked via carbon ornitrogen) with 1-2 heteroatoms, selected independently from O, S and N,which heterocyclic group may bear 1 or 2 substituents selected from oxo,hydroxy, halogeno, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl and C₁₋₄alkylsulphonylC₁₋₄alkyl); 6′) C₁₋₅alkylR³²(wherein R³² is as defined in (5′) above); 7′) C₂₋₅alkenylR³² (whereinR³² is as defined in (5′) above); 8′) C₂₋₅alkynylR³² (wherein R³² is asdefined in (5′) above); 9′) R³³ (wherein R³³ represents a pyridonegroup, a phenyl group or a 5-6-membered aromatic heterocyclic group(linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, Nand S, which pyridone, phenyl or aromatic heterocyclic group may carryup to 5 substituents on an available carbon atom selected from hydroxy,halogeno, amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl,C₁₋₄aminoalkyl, C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy,trifluoromethyl, cyano, —CONR³⁴R³⁵ and —NR³⁶COR³⁷ (wherein R³⁴, R³⁵, R³⁶and R³⁷, which may be the same or different, each represents hydrogen,C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl)); 10′) C₁₋₅alkylR³³ (wherein R³³ is asdefined in (9′) above); 11′) C₂₋₅alkenylR³³ (wherein R³³ is as definedin (9′) above); 12′) C₂₋₅alkynylR³³ (wherein R³³ is as defined in (9′)above); 13′) C₁₋₅alkylX⁶R³³ (wherein X⁶ represents —O—, —S—, —SO—,—SO₂—, —NR³⁸CO—, —CONR³⁹—, —SO₂NR⁴⁰—, —NR⁴¹SO₂— or —NR⁴²— (wherein R³⁸,R³⁹, R⁴⁰, R⁴¹ and R⁴² each independently represents hydrogen, C₁₋₃alkylor C₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 14′)C₂₋₅alkenylX⁷R³³ (wherein X⁷ represents —O—, —S—, —SO—, —SO₂—, —NR⁴³CO—,—CONR⁴⁴—, —SO₂NR⁴⁵—, —NR⁴⁶SO₂— or —NR⁴⁷— (wherein R⁴³, R⁴⁴, R⁴⁵, R⁴⁶ andR⁴⁷ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 15′)C₂₋₅alkynylX⁸R³³ (wherein X⁸ represents —O—, —S—, —SO—, —SO₂—, —NR⁴⁸CO—,—C(O)NR⁴⁹—, —SO₂NR⁵⁰—, —NR⁵¹SO₂— or —NR⁵²— (wherein R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹and R⁵² each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); 16′)C₁₋₃alkylX⁹C₁₋₃alkylR³³ (wherein X⁹ represents —O—, —S—, —SO—, —SO₂—,—NR⁵³CO—, —C(O)NR⁵⁴—, —SO₂NR⁵⁵—, —NR⁵⁶SO₂— or —NR⁵⁷— (wherein R⁵³, R⁵⁴,R⁵⁵, R⁵⁶ and R⁵⁷ each independently represents hydrogen, C₁₋₃alkyl orC₁₋₃alkoxyC₂₋₃alkyl) and R³³ is as defined hereinbefore); and 17′)C₁₋₃alkylX⁹C₁₋₃alkylR³² (wherein X⁹ and R³² are as defined in (5′)above); provided that least one of R² or R³ is other than hydrogen.
 8. Acompound according to claim 1 or claim 4, wherein R⁹ is selected fromthe groups (1), (3), (6) or (10).
 9. A compound according to claim 4 offormula (IX)

where R¹, R², R³ and R⁴ are as defined in claim 4 and R^(y) is hydrogenoor halogeno.
 10. A process for preparing a compound of formula (VIII),which process comprises reacting a compound of formula (X)

where R¹, R², R³, and R⁴ are as defined in claim 4 and R⁸⁵ is a leavinggroup, with a compound of formula (XI)

where R^(x), Y, q and R⁷⁰ are as defined in claim
 4. 11. A method forinhibiting aurora 2 kinase in a warm blooded animal, which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt, or an in vivohydrolysable ester thereof.
 12. A pharmaceutical composition comprisinga compound according to claim 1 or salt, in vivo hydrolysable ester oramide thereof, in combination with a pharmaceutically acceptablecarrier.